Autonomic state in pain and correction

[Diane]

Here is a copy of the disussion in the Five Questions (http://www.somasimple.com/forums/showthread.php?t=2404) thread that led to starting this new thread on autonomics:
(From Barrett: )Wonderful discussion.

Jon,

Your link regarding category mistakes is especially relevant. As some of you know, I'm currently in Las Vegas where my family has gathered to greet my son Alex. He's home from Iraq for two weeks and his stories of searching the road for explosives designed to deceive him fit here perfectly. He says, "When you travel the same road every day you just know when something has changed." Isn't examination of the human body similar in many ways?

I'l be writing more about this.

I think much of this issue revolves around discovering and defending an accurate and relevant essential diagnosis. This doesn't require great leaps in knowledge toward medical school minutia. I think it's wise to leave that to the physician, whether or not he or she does it well.

The third question:: What is your autonomic state and how is that related to your breathing pattern?

Thoughts?
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Barrett L. Dorko P.T.
www.barrettdorko.com

Old 20-05-2006, 10:48 AM #43
EricM
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I observe breathing patterns looking at apical vs diaphragmatic excursion and rate. I ask about the presence of cold hands or feet. However, recently at least for me, the clinical answers to this question have been split roughly 50/50 in similar chronically painful states. This makes me think either I may be missing something in my assessment, or that autonomic imbalance may only be relevant to the patient in question. What I might interpret as 'normal' may be abnormal to the patient and thus still have a significant influence on the pain state.

Eric

Old 20-05-2006, 02:32 PM #44
nari
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I think that many patients consider cold hands and feet 'normal' because they have always had cold extremities. However, in someone who feels quite 'normal' ambient temperature in the extremities, an increased sensation of warmth after contact is informative.
Long before learning SC, I noticed that patients in an altered ANS state had high RRs, often around 25-30, and apical. After some diaphragmatic practising, they reported feeling calmer and their RR decreased; sometimes the pain decreased, and other times, not. They usually put it down to relaxing.
Then I worked out that they needed to practise deeper breathing while moving around; this worked sometimes; and if they practised during neurodynamic movements, they noticed the pain less, which I put down to distraction.
Several patients found a significant difference between breath-holding and breathing during neurodynamic movement. Some found it much better to hold their breath (on a neutral chest expansion, not on inhalation) during the movement. I personally find the same thing - but I know I am the only person to think this fact.

Eric, I agree that sometimes the autonomic state may only be relevant only to the patient in question. I have seen some dire chronic pain people who are quite warm despite their 24/7 pain state. Not sure about this.

Nari

Old Yesterday, 06:52 AM #45
Barrett Dorko
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Nari,

I would say that my experience of this has been remarkably similar to yours.

Hidden within each of the "five vitals of pain" that lead to the questions is something most evaluative schemes do not have: opportunities to teach and learn along with an obvious relevance. Because of this, a great deal of care is provided during evaluation. This certainly shortens the time necessary to treat people. It'll probably cost the therapist money as well. Too bad.

Cooling in relation to those physiologic and behavioral processes that accompany sympathetic increase is the "physiologic signature" of the abnormal dynamic. I know that there are patients who aren't cold and should be but typically they're good diaphragmatic breathers for some reason, most commonly chior or yoga. In any case, this third question gives me the opportunity show them how these things relate to their discomfort and thus draw them further toward a realization that much of their pain is a consequence of their behavior - behavior they can control.

Abnormally warm people are also out there. Most of the time they have mid-thoracic issues and, I presume, are dysautonomic. I've seen this improve dramatically coutless times. I have no way of proving that of course, so I make no claims.
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Old Yesterday, 07:51 AM #46
Diane
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Lately I treated a woman who is one of the warm ones. She even said, "My feet get so hot that they burn.. I strap ice packs to them so I can go to sleep." She certainly had lots going on between the blades...

The autonomic system has always flummoxed me. I've never understood it well enough to be able to convince myself I can predict what it can/will do, or that anyone else who sounds like they have it down pat, really does. And I've never believed that popping backs somehow enhances or normalizes its function.

I've just acquired another Burnstock book, called Comparative Physiology and Evolution of the ANS.. Haven't started it yet.. if I can make head or tail of it, I'll let you know. All I know right now is that in lots of different species including our own, autonomics make skin change color and hair lift up. Also that skin has ten times the amount of blood flow it needs for its own maintenance, so it can be a metabolic heat radiator/entropy radiator. Meanwhile, for pain, I think it's safe to say that producing any kind of change in autonomics into the opposite direction of wherever they seems stuck, is beneficial. Maybe the rule could be, if it's cold make it warm, if its hot, make it cool.

The other big clue I got was finding out not that long ago that autonomics do the opposite thing in the skin than they do in muscle. I'm still composting that. It's so big that it's taking quite awhile.. it makes sense that the blood shunting mechanism would be different for mesoderm than for ectoderm and endoderm, thinking embryologically. It makes me more convinced than ever that skin is the key to the mansion, not only for pain diminishment but also for autonomics.. just trying to work out why and how.
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Diane


Old Yesterday, 08:48 AM #47
Jon Newman
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Hi Diane,

You may be interested in the following. This is a side bar and if anyone wants to discuss it further maybe a new thread can be started. The current one has a good flow right now but I do think this is pertinent to the discussion.

One of the poster presentations at the APS conference was titled Skin potential as a measurable correlate of moderate to severe chronic pain--a case report and was authored by Donald D'Angelo.


Introduction

There exists a perceived need for an objective measure of pain and pain relief. There is a device used in veterinary medicine to perform bilateral measurements of the electric charge of the skin, skin potential (SP). SP can be used to detect distinctive asymmetries caused by the autonomic nervous system as it responds to moderate to severe persistent pain. SP can accurately reflect changes in the ANS. The goal of this study was to determine if this device might reliably assess pain in humans.

While the methods and results are certainly important, I will simply summarize as this is 'only' a case study. The measuring device is trademarked as PainTrace manufactured by Biographs LLC, Bayville, NY. Here's a quick summary of what they are measuring:

If both palms produce equal voltage, the linear trace will be a flat, horizontal line down the center of the graph paper. We take this line as the X axis of our graph, with the arrow of time to the right. This functions as a neutral baseline with a value of zero. When the right palm is producing higher SP than the left, the linear trace will be above the neutral baseline on the graph. When the right palm is producing lower SP than the left, the linear trace will occur below the neutral baseline.

The picture they show is simply a nickel sized electrode placed in the palm of each hand with the leads running to a chart recorder.


The asymmetrical SP can be accounted for by the ANS innervation of the skin. It has been found in numerous mammalian species that an autonomic response is demonstrated with persistent pain. At the onset of acute pain, the ANS raises sympathetic tone and accordingly blood pressure and heart rate, which have been shown to normalize with respect to time. The activation of baroreceptors by elevated BP, triggers an increase in vagal tone in an attempt to restore homeostasis. This increase in vagal tone has been demonstrated to provide an opioid-mediated partial anti-nocicipetion in both animal and human models. The primary pathway for this effect is mediated via the right cardiac vagal trunk. In addition to the heart, the vagus affects other physiologic changes including a lowering of SP. Thus, during moderate to severe chronic pain, skin on the right side has a lower SP than on the contralateral side, while mild pain fails to trigger the baroreceptors and therefore does not produce changes in SP. After pain relief, vagal tone moves back towards normal, with a coincident fall in SP on the right side.

This D'Angelo fellow by the way is an MD working for New York Harbor VA medical center in the dept. of anesthesiology.


Summary: In all five sessions for this individual, SP was lower on the right side during moderate to severe chronic pain (VAS 4-10). After pain relief, SP on the right rose. Distinguishing between painful and pain-free states in this patients was as simple as seeing whether the trace was above or below the neutral baseline.

It will be interesting to follow whether this technology, if validated, comes into play in future pain studies.

Old Yesterday, 09:08 AM #48
Diane
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Thanks Jon.

At the onset of acute pain, the ANS raises sympathetic tone and accordingly blood pressure and heart rate, which have been shown to normalize with respect to time. The activation of baroreceptors by elevated BP, triggers an increase in vagal tone in an attempt to restore homeostasis. This increase in vagal tone has been demonstrated to provide an opioid-mediated partial anti-nocicipetion in both animal and human models. The primary pathway for this effect is mediated via the right cardiac vagal trunk. In addition to the heart, the vagus affects other physiologic changes including a lowering of SP. Thus, during moderate to severe chronic pain, skin on the right side has a lower SP than on the contralateral side, while mild pain fails to trigger the baroreceptors and therefore does not produce changes in SP. After pain relief, vagal tone moves back towards normal, with a coincident fall in SP on the right side.
It still doesn't make sense yet. In other words, I still can't quite "see" it yet. I see a vague random rise and fall, sort of like the sea heaving around but I can't make out what is calming it down and what is making it rise. My confusion is directly proportional to the lack of focal length/ability to see a big(ger)/ the big(gest) picture, and was based originally on a category mistake named "peripheral/central" instead of "ectodermal/mesodermal/endodermal".

Other thoughts/beliefs I've held about the ANS that need closer looking/ deconstruction:
1. parasympathetic good for pain, sympathetic bad for pain
2. touching improves parasympathetic function
3. exercise increases sympathetic function
4. autonomics are essential for breathing, digestion, heart function
5. that there must be consistency somewhere in it that I'm missing (maybe there isn't any consistency or fixedness or predictability, maybe there is only perpetual dialectic)

Definitely, let's start a new thread. (I started one awhile ago.. can't find it just now.. I posted a picture of an interneuron. The thread died and got lost. I'll repost the picture.)
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Diane


Old Yesterday, 03:36 PM #49
Barrett Dorko
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A new thread about the autonomic state in pain and during correction sounds good. To me, it's the least well understood portion of the "five vitals" equation. Jon's attendance to that conference is really paying off for all of us here.

Time for the fourth question : Which ways do you want to move and how does that make you feel?

I always ask my classes at this point - How do I ask this question?

Any takers?
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Barrett L. Dorko P.T.

[emad]

Diane,thanks for setting this new thread for ANS ,it is worth as it is directly related to the severity or degree of pain in most of the patients we encounter and i think it is direct relation between the psychological and physical matters of the body .

Regards
Emad

[Diane]

You're welcome Emad.:)

While I was doing a comparison between Grieve's 2nd and Grieve's 3rd editions of Modern Manual Therapy, I re-discovered Chapter 20 in the 2nd ed, by Grieve, called "The autonomic nervous system in vertebral pain syndromes".
Apart from the juxtaposition of the words "vertebral" and "pain" (as in the adjective vertebral modifying the noun pain, as if the mesoderm were largely respoonsible for back pain..) the article is a run down of the ANS up to 1994.

Here is a summary, paragraph by paragraph. The intro starts with a quote from Lewis Thomas in 1984:

INTRO:
The greatest difficulty in trying to reason your way scientifically through the problems of human disease is that there are so few solid facts to reason with. It is not a science like physics or even biology, where the data have been accumulated in great mounds and the problem is to sort through them and make connections on which theory can be based.

Alrighty then..
Paragraph 1:
- nervous system is a continuum, word "autonomy" (from Langley 1898) is misleading, suggests it works in isolation;
- Williams et al (1989); although connections with somatic elements not always clear, evidence exists for visceral reflex activity stimulated by somatic events including trauma;
- term "PNS" includes cranial, somatic visceral and splanchnic nerves (Fig. 20.1-20.5); better term is "involuntary"

2.
- autonomic and somatic divisions originate together from same basic units or neurons (her doesn't name neural crest specifically but that's where they come from) associated in similar reflex arcs; related structurally and often closely connected (Mitchell 1954);
- somatic and autonomic parts are more alike than different;
1. The essential morphology and arrangement of afferent neurons is similar in somatic and visceral systems, yet it is incorrect to speak of 'afferent autonomic neurons' since the symp and parasymp systems are purely 'outflow' systems and are thus entirely efferent (Wyke 1990). The phrase 'visceral afferent neurons' is employed by Williams et al (1989).
2. The dorsal spine roots convey afferent traffic from soma and viscera alike; the dorsal spinal ganglia contain nerve cell bodies of visceral as well as somatic afferents.
3. It has been shown (Pomeranz et al 1968) that the small-fibre nocioceptive afferents from both somatic tissues and viscera converge in the substatia gelatinosa cells. Somatic and visceral afferent fibres conveying nocioceptive impulses have the same histological appearance, being mainly unmyelinated neurons with diameters of 0.2-1.5 um (although some somatic nocioceptive afferents may be up to 4.0 um in diameter) (Williams et al 1989).
4. There are further similarities between the two systems in that axon reflexes can be elicited at terminals of autonomic postganglionic fibres (Williams et al 1989).
5. The phenomenon of peripheral axonal sprounting occurs in sympathietic nerve fibres as in somatric nerves (Shafar 1966).
6. Degenerative changes in the autonomic system are the same as in the somatic system (Williams et al 1989). After injury, autonomic nerves demonstrate great regenerative capacities (Brodal 1981).


- "Musculoskeletal pain and associated symptoms cannot be considered in isolation from concomitant changes in autonomic neuron activity."

SOMATOVISCERAL/VISCEROSOMATIC REFLEXES
paragraph 1.
- Gaskell (1961) proposed studying ANS in terms of reflexive behavior;
2.
- list of researchers between 1945 and 1978;
3.
- segmental innervation, Head 1920
4.
- facilitated segment, Denslow et al 1947
- Kostyuk confirmed relation at the posterior horn 1968, showed "afferents from viscera can cause presynaptic inhibition upon somatic afferent impulse traffic" and also "exert postsynaptic inhibition which is under supraspinal modulatory control from the bulbar reticular formation."
- Pomeranz et al 1968 showed that "visceral afferents inhibit the effect of converging afferents from the skin and conversely, stimuli to the skin can cause inhibition of neurons on which visceral afferents terminate."
- same mutual inhibition is exhibited by group III afferents from skeletal muscles and skin.
- thicker neurons penetrate deeper into dorsal horn, as a rule;
- unmyelinated Cs terinate in laminae I and II;
- some small myelinated A-deltas may get as far as layer V;
- large myelinated cutaneous afferents get to III, IV, and V;
- largest sensory aferents from muscle reach lamina VI.

5.
- laminae I and II are major layers for nocioceptive reception;
- "nocioceptive collaterals in deeper layers are polysynaptic and are active in initiating visceral and somatic efferent traffic, producing changes in autonomic function and skeletal muscle as a consequence of nocioceptor input."

6.
- nocioception from viscera travels in splanchnic nerves, probably enters spinal cord via white rami communicantes and dorsal spinal roots; then evidence suggests it occupies the lateral spinothalamic tract (Williams et al 1989);

7.
- collaterals of the ST tract recruit more autonomic activity, relay it through the periaqueductal grey matter to nuclear cuneiformis and on from there to hypothalamus;

8.
- viscera insensitive to cutting, burning or crushing, but react to excessive tensioning; referral cutaneously is common; once peritoneum becomes involved, e.g. inflammation, spasmodic pain in the region results;

9.
- painful skin area/referrral zone "acutely tender", "cutaneous vasoconstriction" may be evident;

10.- "Conversely, pain unaccompanied by a greater or lesser degree of visceral reflex activity, e.g. one or more of changes in pulse rate, blood pressure, vasomotor and temperature changes, sudomotor activity and pupilliary diameter, has not been described."

11.
- autonomic reflex activity not initiated solely by general visceral afferent pathways;
- "In most instances demanding general sympathetic activity for effort, the afferent element is usually somatic, from the special senses or the skin. Rises in heart rate, blood pressure and pupillary dilatation may result from somatic receptors in the skin and other tissues. Conversely, contraction of the muscular abdominal wall - a somatic structure - often results from irritation of abdominal viscera. Also, axon reflexes may be evoked by stimulation at the terminals of autonomic postganglionic fibres (Willams et al 1989)." (emphasis mine)

More to come. Next, Musculoskeletal pain and concomitant features.

[Diane]

Musculoskeletal pain and concomitant features
Paragraph 1:
- all the symptoms evoked by spinal joint nocioception.. "All were relieved of these symptoms by manual treatment to the T5-6 segment and adjacent structures." (pallor, sweating, bradycardia, fall in BP, feeling of faintness, nausea..)
2.
- familiar experiences, borborygamous provoked by mobe- ing T5 in prone patient, cold sciatic leg, etc.. (shopping list of autonomic states connected to spinal manual therapy or stress of T spine... no mention of any other sort of treatment or of another location initiating autonomic changes)
3.
- confusion from tenderness of abs.. easily referrred pain from T spine..
4.
- myofascial "trigger points" mentioned.. thought to be capable of disturbing visceral function -> somatovisceral
5.
- viscera can refer to skin and also to skeletal muscle -> activate trigger points..; "myofascial pain may initiate vascular changes, e.g. variation of skin temperature, reddening of cunjunctiva and secretory changes like coryza, lacrimation, localized sweating and pilomotor changes as 'gooseflesh'."
6.
- facial pain..close association of trigeminal nerve with autonomic ganglia.. more about trigger points.. mention of idea of vertebral joints affecting visceral conditions being a tad outdated..
7.
- mention of former notions of manip as "soverign remedy for all ills, visceral as well as musculoskeletal"

SO-CALLED AUTONOMIC PAIN
Paragraph 1
- various coined and arbitrary classifications of pain
2.
- the phrase "autonomic pain" "may be attractive"..
3.
- how electric/mechnical stim of various sympathetic ganglia has led to pronounced pain states/anxiety
4.
- Nathan 1976 -> "refers to visceral afferent fibres conveying both visceral sensation and pain. Whether this is called 'autonomic pain' seems a matter of semantics."
5.
- local anaesthetic into sympathetic nerves to treat neuralgia of ulnar nerve
6.
- drawback: if term such as 'autonomic pain' is proposed, another term like 'somatic pain' follows, and then differences must be drawn.. besides, autonomics are efferent.
7.
- Bogduk 1983 -> reviewed clinical features of causaligia and RSD, said that "in sympathetic pain syndromes affecting the limbs, the mechanism of pain lies in the somatic and central nervous systems - 'whatever sympathetic features occur are only epiphenomena superimposed on this pain.' "
8.
- Melzack and Wall (...finally!); fibre diameter not enough, may be completely irrelevant, in explaining origin of pain in neuropathies;
- sympathetic effector neurons have crucial role in exciting somatic afferent sensory fibres, idea originally proposed by Richards 1967..;
- e.g. nerve injury, neuroma forms after nerve transection;
- axon sprouts "show marked spontaneous ongoing activity without apparent stimuous"
- sensitive to noradrenalin whether applied directly or in blood vessels supplying the neuroma (See AIGS thread);
- "A mixed nerve inevitably contains sympathetic efferent fibres, and since new axon sprouts a temporarily devoid of the tubular insulating myelin sheath small numbers of adjacent neurons begin to excite each other i.e. ephaptic transmission (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6255143&dopt=Abstract) or 'cross talk between fibres' (Melzack and Wall 1982)."
- "Thus sympathetic neuron effector traffic, at the site of injury, is transposed to adjacent afferent neurons as sensory stimulation. This superimposed afferent traffic reflexly triggers even more sympathetic neuron output, so that the limb is not only painful but glossy and moist."
9.
- discussion of the drug guanethidine, persistent pain, central pain... "Perhaps the phrases 'autonomic pain', 'sympathetic pain', or 'parasympathetic pain' have about as much validity as the phrase 'somatic pain', perhaps there is only pain, with the inescapable degree of autonomic reflex activity sometimes overwhelmingly and disasterously to the fore."

Next: THE POSSIBLE BASIS OF SOME CLINICAL FEATURES

[Jon Newman]

I'm getting close to wrapping up some of the things I learned at the APS conference this year but I've got a few things left. I went to a lecture titled "Cardiovascular and pain regulatory system interactions: Implications for hypertension risk and chronic pain." I figured this was the best place to hear something about the ANS and pain. Unfortunately I'm not that much clearer on the topic partly because I don't have a deep enough understanding to appreciate all that was being covered and partly because it is so complex, even for those whose career is centered on the topic. But I'll try to add some things I found interesting. I'll add the thoughts of three different presenter's in three different posts. First up, Christopher France (http://www.psych.ohiou.edu/people/faculty/france/france.html) discussed "Hypertension, risk for hypertension and pain".

Apparently hypertension and risk of hypertension are associated with hypoalgesia. They found decreased pain in humans with hypertension(HTN) during electrical tooth pulp stimulation, thermal stimulation and mechanical stimulation. They also found that normotensive individuals at risk for HTN (e.g. parental history, current high blood pressure) exhibit hypoalgesia.

He presented information that demonstrated that the hypoalgesia present in individuals with HTN or at increased risk for HTN does not appear to be mediated by enhanced endogenous opiate activity--this theme was reiterated through all lectures.

Something mentioned only in passing during the lecture but which I found very interesting is that once someone knows they are hypertensive they are no longer hypoalgesic. I'll try to tie in some autonomics in the next post.

[Jon Newman]

The next speaker was Mustafa al'Absi (http://www.d.umn.edu/~malabsi/mustafa.htm) whose presentation was titled "Adrenocortical responses to opioid blockade in hypertension prone men and women."

I'll provide some "bullets" from his powerpoint presentation much of which builds on my last post and ties in with my next (whenever that happens).

--Pharmacologically increased PB reduces pain avoidance.

--The presence of adrenal steroids varies directly with hypertension risk in animal models of hypertension

--Enhanced activation of autonomic controlling centers of the hypothalamus and medulla in individuals at high risk for HTN.

--Enhanced sympathetic and hypothalamic-pituitary-adrenocortical (HPA) axis activity

If I understood correctly endogenous opiates have an inhibitory effect on cortisol response in terms of timeline--Specifically cortisol levels increased following pain assessment after the ingestion of naltrexone, but not placebo. The low HTN risk group exhibited an earlier peak of cortisol response.

Lastly, he reiterated that hypoalgesia in HTN-prone individuals does not appear to be mediated by enhanced endogenous opiate activity.

I've got some references for "suggested readings" from all the presenters if anyone is interested.

[Diane]

I've got some references for "suggested readings" from all the presenters if anyone is interested.

Some new/recent references would be great!

Thanks for adding your posts. This thread will likely be more a repository than a discussion.. which is just fine.. a space for spreading out inventory before decluttering/doing a yard sale.

[stregapez]

So, do cold hands and feet often correspond with sympathetic activation? And do they often correspond with high blood pressure? Am especially curious, as , like i sad, I have sort of cool-prone hands (mostly the right one lately), and used to have cold hands /feet. Have always had low (low-normal) blood pressure. According to a saliva test done a year 1/2 ago, and a pharmacist who interpreted it, I have low cortisol levels too. No idea what that means. He suggested they were possibly depleted "from stress," and another pharmacist who worked in the same place tended to disagree and suggested it's because I am "laid-back." Me, I can never figure out if I am very laid back or just totally stressed :)

Dana

[Diane]

THE POSSIBLE BASIS OF SOME CLINICAL FEATURES
1. Dissemination and amplification of autonomic effects
2. Cranial symptoms after cervical injury of secondary to upper cervical arthrosis
3. Musculoskeletal changes as lesions of trespass
4. Autonomic nerve involvement in referred pain and other symptoms

The rest of the chapter is the elaboration of these 4 points, and a bunch of diagrams, which I will bring later.

Here is another thread that died a premature death, on the topic of autonomics (http://www.somasimple.com/forums/showthread.php?t=2348), which features a depiction overall.

[emad]

Diane ;

Good topic .

#
You or the writer you copy from back again the concept of Trigger
points ,which since at least 3 years i had begun to put it behind ,because
of lack of scientific evidence .

#
Seems you or Jon copy views of medical schools whom sometimes i believe
they look at pain issues as arthrosis ,arthiritis ,systematic ,,joints ,,,,.For
example ,most of cervical cases they look at as cervical spondylosis .

#
In general,the topic is very interesting as it discuss a feature of pain cases which we usually we meet as patient,s complaints .

Regards
Emad

[Diane]

Good points Emad.
You or the writer you copy from back again the concept of Trigger
points ,which since at least 3 years i had begun to put it behind ,because
of lack of scientific evidence . Agreed. Apparently Grieve was still thinking about them in 1994 when this text came out, along with lots of other mesoderm.

[Diane]

Page 297:
1. Dissemination and amplification of autonomic effects
When examining and treating patients, reliance on the classical anatomical facts of autonomic nerve arrangement, and the older physiology of neural traffic in autonomic ganglia and at effector endings, may be insufficient in terms of appreciating the possible basis of clinical features. I like this.. it signals humility in the face of a fractal nervous system.
Structural and functional examples of dissemination and amplification of autonomic effects

Structure
The classically-described distribution of autonomic nerves is sketched in Figures 20.1 - 20.5, yet the segmental levels of outflow for sympathetic efferent neurons (Johnson & Spalding 1974, Williams et al 1989) are not universally agreed. Some authors place the sympathetic supply to the heart beginning as high as C3 (Lindahl & Hamberg 1981). Continental anatomists (Tinel 1937, Laruelle 1940, Guerrier 1944, Delmas et al 1947) reported the cell bodies of preganglionic sympathetic neurons in the cervical segments C5-C6-C7-C8 and joining these somatic roots, although many give the uppermost as T1. The French authors stated that the rami communicans from these neurons also mank synaptic junctions with the small sympathetic ganglia developed around the vertebral artery in the foramen transversarium between C4 and C6.

On the other hand, Bogduk (Ch.22) observes that 'the so-called "vertebral nerve" consists of no more than grey rami communicantes accompanying the vertebral artery - stimulation of these nerves in the monkey failed to influence vertebral (artery) blood flow.'

Variations, between a purely preganglionic and postganglionic arrangement, are described. In addition to white and grey rami, mixed types occur. In the cervical region, bundles of thick myelinated fibres join the grey ramus to reach the prevertebral muscles, and at thoracic segments grey and white rami may be fused (Williams et al 1989).

Day (1979) mentioned that it is difficult to state precisely the source of all the nerve fibres (particularly sympathetic) supplying a given tissue.

Peripherally, the extent of segmental areas innervated is variable. There is considerable overlap of supply by adjacent nerves. The innervation by different effector systems, e.g. vasomotor and sudomotor, of a particular nerve are not necessarily the same. Textbook descriptions of autonomic innervation differ considerably. There are special differences, as well as variations between individuals.

Schemes such as these shown in Figures 20.1-20.5 are no more than simplified summaries. It is probable that the full detail of distribution is much more complex. Williams et al (1989) allow the possibility of a limited outflow of preganglionic fibres in other spinal nerves, and mention the certainty that 'nerve cells of the same type as those in the lateral grey column also exist at other levels, above and below the thoracolumbar outflow (Mitchell 1953), and that small numbers of their fibres issue in corresponding ventral roots.' Operative findings indicate that many individuals do not have a symmetrical arrangement to the upper limb, and it is known that prefixation and postfixation occurs, as in the somatic limb plexuses (Johnson & Spalding 1974). Increasing deterioration of autonomic nerve function in ageing reflects the increasing occurrence of Wallerian degeneration and segmental demyelination. Regeneration does not keep pace with successive degenerative events. Appenzeller and Ogin (1973) suggested that functional deterioration may in part be attributed to changes in the myelinated fibres (white rami communicantes) of the paravertebral sympathetic chain.

Is it any wonder we get so confused about how this works when it is structurally, anatomically, and behaviorally so variable?
Next, Function.

[Jon Newman]

Here's one article (http://hyper.ahajournals.org/cgi/content/full/41/6/1228) Diane, as I've stated, the information is confusing--at least to me. Sticking with the confusion theme I'll add some thoughts from the last presenter. While the first two presentations focused on hypoalgesia in HTN, the last presenter, Ok Yung Chung (https://medschool.mc.vanderbilt.edu/brain_institute/php_files/faculty_blurbs.php?ID=1806) looked at whether chronic pain is a risk factor for HTN. Here's some highlights

Chronic pain as a prolonged stressor can:

--elevate blood pressure and increase the risk of cardiovascular disease by stimulating the sympthethic nervous system

--result in slower recovery from the release of adrenal hormones


--Healthy controls show effective opioid modulation of SBP recovery and return to baseline following acute pain stressor

--Chronic pain patients do NOT return to baseline and show NO opioid modulation

Sympathetic nervous system in HTN

--contributes to the initiation and maintenance of HTN
--SNS activity is heightened by impariment of cardiovascular reflexes (baroreceptor reflexes)
--Causes vasoconstriction
--Enhances sodium retention
--creates trophic effects on blood vessels
--results in abnormalities in ion transport

I've got to stop now but next up is "Links between pain pathways and the autonomic nervous system"

[Diane]

Thanks Jon.
More please.
One thing that can be said about the autonomics that I forgot to mention in my little list way back when, is how related their function is to cognitive/social/emotional states. They are like ideomotor movement that way.

Here are thumbnails from the Grieve's article.

[Jon Newman]

While pinning down the interaction of the ANS and pain is confusing it perhaps isn't nearly confusing as my lead in sentence to my last post. Hopefully what follows is written more coherently.

More bullets from Ok Yung Chung

--Common anatomic sites exist for the generation of both HTN and chronic pain

--This "central autonomic network" controls and coordinates visceromotor, neuroendocrine, pain, and behavioral responses essential for adaptation:

Insular and prefontal cortices
Amygdala
Hypothalamus
Periaquaductal grey (PAG)
Parabrachial region
Nucleus tractus solitarius (NTS)
Ventrolateral medulla (reticular zone)

I kept in the anatomy part just to be thorough, not because I actually know where all this stuff is exactly (and also so the following makes more sense).

Pain and blood pressure: reciprocal process

Increased BP-->Baroceptor activation-->Activates NTS-->Inhibits rotral ventral medulla-->increased descending pain inhibition and decreased SNS outflow-->decreased BP

Depressed baroreflex functioning may be due to dampening of the sympathetic inhibitory centers (NTS) and preservation of centers that exert a positive modulation of sympathetic tone (rostral ventromedial medulla or RVM)

Maybe those semesters in neuroscience were important after all. If I'd only paid attention.

Links between pain pathways and the ANS

--Vagal baroreceptor afferents to the NTS send descending afferents to the autonomic centers of the spinal cord

--The hypothalamus coordinates autonomic and sensory information, including ascending spinal nociceptive signals, and elicits antinociception via links to the NTS, PAG, and RVM (NRM) which ultimately trigger the activation of descending noradrenergic pathways.

--The medial preoptic nucleus projects to the PAG and the RVM. It has an important role in the autonomic response to pain.

--The brainstem locus coeruleus:

Provides norepinephrine to all major levels of the neuroaxis including cardiovascular regulatory areas (e.g. ventral medulla, NTS) and pain inhibitory areas (e.g. NRM via alpha-2 adreneric receptors)

Integrates afferent information from the baroreceptor centers and the limbic system, thereby influencing sympathetic tone.

--The amygdala is a critical region for mediating the expression of autonomic, neuroendocrine, and behavioral changes that occur in response to fearful or aversive stimuli, such as pain.

I don't know about you but that's enough for right now. This particular lecture was full of interesting info. There is more pathway type information (specifically, opioid system and the RVM and Adrenergic system and the RVM) that I suppose I can provide if people are dying to know but otherwise I'll try to capture some other interesting factoids that I feel may be pertinent and post them in my next entry.

[Diane]

Jon, give us everything you've got. As long as your fingers hold out. And including the anatomy would be really good.

Function
The presence of intermediate sympathetic ganglia (Boyd 1957), and independent sympathetic connections, implies a multiplicity (Erhlich & Alexander 1951) of neural pathways much richer than classically described (see also fig. 20.12). Some 50 years ago, van Buskirk (1941) described ascending sympathetic neurons from as far caudal as the seventh thoracic segment. He quotes the work of Smithwick (1936) who reported that complete sympathetic denervation of the upper extremity in the monkey, by section of the anterior roots of thoracic nerves, requires section of all the roots down as far as the twelfth thoracic segment.

The earlier concept of autonomic ganglia as mere relay stations has been much broadened by work in the fields of electron microscopy, neurohistochemistry and electrophysiology (Williams et al 1989).

The variety of neuron types in autonomic ganglia is known to be much greater than previously implied by the simple, dualistic terminology of 'preganglionic' and 'postganglionic'. In the superior cervical sympathetic ganglion, the ratio of preganglionic to postganglionic neurons may be 1:175, for example (Ebbesson 1968). There are wide variations in individuals of the same species (Gabella 1976), e.g. from 1:63 to 1:196 in man - a substrate for the wider dissemination of sympathetic effects than a simple 1:1 relationship. This characteristic is not exhibited to such a degree by parasympathetic ganglia. New knowledge also suggest the phenomenon of amplification of sympathetic effects, and mechanisms underlying this characteristic may be (a) widespread terminal arborization of preganglionic neurons, (b) the mediation of interneurons, (c) the paracrine effect, i.e. intraganglionic diffusion of loically produced transmitter substances and/or endocrine effect, intraganglionic diffusion of substances conveyed from elsewhere.

All of these mechanisms may amplify effector activity.

Next, vascular channels, synapses, and interneurons. All this is still under point 1., Dissemination/amplification.

[Jon Newman]

Alrighty then, for Diane (still info. provide by Ok)

Opioid system and the RVM:

--The RVM receives its major inputs from the midbrain structures, PAG and culeus cuneiformis, and from the limbic and prelimbic cortex.

--The PAG and RVM contain opioid receptors and the PAG-RVM connection is critical for both pain modulation and integration of autonomic and somatic reactions, including the baroreflex.

--There are three distinct populations of neurons in the RVM
ON cells (facilitate nociception)
OFF cells (inhibit nociception)
Neutral cells (no consistent change)

--REVM OFF cells are activated and ON cells inhibited when mu-opioid receptor agonists are given systematically in the PAG or directly in the RVM.

Adrenergic system and the RVM

--The RVM receives dense catecholaminergic innervation. The locus coeruleus (A6) and the medullary pontine cell groups (A1, A2, A5, A7) are the hypothalamus, thalamus, and spinal cord.

--The noradrenergic system does not appear to be tonically active. Noradrenergic neurons may be recruited by activation of the PAG or RVM.

--Norepinephrine has opposing effects at alpha-1 and alpha-2 receptors, with alpha-1 agonists facilitating, and alpha-2 agonists inhibiting nociceptiv transmission.

I'll add other, perhaps more digestible, information later. If I'm not back in five minutes... just wait longer.

[Diane]

You're a funny man, Jon..:star:

(Still under 1. Dissemination and amplification of autonomic effects: )
Vascular channels:
The vascular connective tissue stroma of ganglia is linked to perineural spaces by minute channels, possible avenues for movement of neurotransmitter and hormone substances between neurons, and between these and blood vessels. Aha.. the ganglia is a leaky boat. That makes sense; if a ganglia is a place that processes regional information (like a big pre-brain chat room) it makes sense that it would be as communicative within itself as it could possibly be, through interconnectedness and neuro"chemically".
Synapses:
In the nervous system as a whole, synapses between neurons involve the junction of almost any part of the neuronal surface. Electron microscopy reveals many types, classified by neuronal processes involved or direction of transmission, e.g. the most frequent axo-dendritic, the quite common axosomatic, and also axoaxonic, dendroaxonic, dendrodendritic, somatodendritic and somatosomatic types. Everyone got that? Anything neural can touch anything neural and make a synapse apparently.
The terms reflect the morphology of the junctions. Axodendritic and axosomatic synapses are found in autonomic ganglia (Williams et al 1989). While axosomatic synapses are lerss numerous, sympathetic ganglion neurons reveiver great numbers of axodendritic synapses from preganglionic fibres, forming several synapses with numerous separate dendrites - perhaps representing the mechanism for dissemination or amplification or both. The mode of termination of preganglionic axons is highly variable (Brodal 1981). It doesn't say, but I'm guessing that means, from one individual to another..

Interneurons:
Most ganglion cells are large (25-50 um diameter) and multipolar. Smaller and less numerous cells (15-20um), clustered in groups and less multipolar in shape, have been identified in sympathtetic ganglia and are probably interneurons. These 'small intensely flourescent (SIF) cells (Evanko 1978) contain catacholomine neurotransmitters, their supposed action being the release of dopamine which unites with the surface receptors of ganglionic neurons and modifies impulse transmission patterns. Types I and II SIF cells have been described, and there is evidene that type II cells pass their secretions into local blood vessels (see above), thus exerting more diffuse and distant effects.

Brodal (1981) mentioned the many unsolved problems relating to structure and functional organization of autonomic ganglia.

I found lots there to satisfy my appetite for anatomical minutiae. Plus I'm starting to think we should get whatever this Williams person was busy doing in 1989, since most of this chapter seems to derive from it.
Next is point 2., Cranial symptoms after cervical injury or secondary to upper cervical arthrosis.

[emad]

Diane & Jon :

The last posts are so academic ,thanks for posting , i try to survey as possible , i read what i like or interested in .

Anyway , i liked the last image ,but it is too small , i can not enlarge it , i hope bernard reads me now to find what we can do , i download it but can not read around the image .

Regards
Emad

[Diane]

2. Cranial symptoms after cervical injury or secondary to upper cervical arthrosis

Long section, notes only.
paragraph 1.
- Barre-Lieou syndrome from 1926; headache, vertigo, tinnitus, ocular problems;
- was found in conjunction with cervical arthrotic changes;
- more prevalent with increase in MVAs especially rear-enders; neck pain more common after rear impact (84%, Deans et al 1986);
- the shorter the impact time the greater the rate of change of velocity or acceleration;
2.
- "Injury to the cervical spine is almost without exception due to indirect violence (von Torklus & Gehle 1972), the force being applied to head or rmp and the neck sustaining a considerable proportion of it."
3.
- multiple "sprained ankles" in the neck (lots of mesodermal emphasis)
4.
- headache mechanisms
- injuries on atheletic field
5.
- fall in a shower
6.
- these cases present with one or more of:
-Suboccipital, neck and yoke area pains, unilaterally or bilaterally, with bouts of frontal headache which may be periodic and transient or remain as a dull and constant background ache
- Facial and anterolateral throat pain
- Patches of subjective facial numbness
- Otalgia
- Retro-orbitial pain - sometimes paraesthesiae 'in' the eye
- Subjective laryngeal disurbances, with compulsive clearing of the throat
- Upper pectoral area and axillary pain
- Feelings of instability or dysequilibrium, with sometimes a tendency to list to one side
- Disturbances of hearing and/or vision
- Depression, and feelings of fatigue
- A belief that they are becoming neurotic and 'should pull themselvers together'
- Irritability, insomnia and light-headedness
7.
- Roca (1972); blurred vision, strain, fatigue, diplopia, photophobia, inability to read, anxiety, depression;
- amaurotic episodes, decreased accomodation and convergence, anisocoria, possible vitreous detachment, hyperphoria, hypertropia, ptosis, inability to focus
8.
- Downs & Twomey (1979); symptoms are credible;
- patients tend to move the neck cautiously, apprehensively, seek neutral comfortable positions
9.
- Worth (1985); less sagittal segmental mobility at the OA segment although xrays are normal usually

(long section on radiographic investigation... C4 root sleeves often show defects.. suprascapular region often weakish.. fusions etc. (:cry:) )
Comment: This report is described in some detail because of its salient findings, a consistent involvement of the C4 root sleeve in 'whiplash' syndrome. The findings at myelography and at operation were of lateral 'soft' disc herniations at C3-4, exerting trespass not directly on the spinal cord but on the C4 root and more so the ventral root. The author enlarges upon the C4 root communications with the superior cervical ganglion, via branches of the postganglionic fibres, and suggests that irritation of the C4 root compromises the function of these communications, thus resulting in symptoms related to the sympathetic nervous system. He also mentions, among other observations, that tinnitus might be produced by sympathetic stimulation of the caroticotympanic nerve, and that ocular symptoms may be produced by the aberrant influence of the internal carotid plexus on the ciliary muscles or by reduced flow in the opthalmic artery. Maybe, maybe not.
Again, the connections between the upper cervical nerves with the vagus, accessory, and hypoglossal nerves, through the superior cervical ganglion, have been postulated as the substrate for the cervical spine's ability to produce the synptoms described (Campbell & Parsons 1944, Braaf & Rosner 1975). His explanation of the production of symptoms may be speculative to a degree (see also Grieve 1988), but the segmental identification of a consistently involved nerve root sleeve is a decided step forward in management, whether by surgery or conservative treatment of these distressing syndromes. The rest is all on handling and difficulty of prognosis. Slow recovery, need to be gentle (duh..). No great insights into how to handle, which in his view is all about mobe-ing. Sure. The neck loves that. (not.) Nothing here about how to unload the nervous system/C4 nerve root sleeve, by considering everything that might be affecting it and working from the outside in instead of trying to barrel directly in on it. Oy.

Next, 3. Musculoskeletal changes: lesions of trespass. Some photos of osteophytes that are huge. Think I'll skip them.

[Jon Newman]

Those who can admit to liking Jim Carey might recognize the opening and closing lines of my previous post were borrowed (alright, stolen) from Ace Ventura. Now, more than 5 minutes later, here's some more riveting reading. Any neuroscience profs reading? Please feel free to add your thoughts.

Norepinephrine, a common neurotransmitter for chronic pain and hypertension

--Is released in the spinal cord by acute somatic (noxious) stimuli

--Mediates antinociception elicited by acute induction of hypertension

--Modulates nociceptive information in the dorsal horn prior to its transfer to higher centers

--Is implicated in descending antinociceptive activity elicited by stimulation of the PAG, via a RVM-A7 link in the NRM (got that?)

--Is involved in controlling mood, arousal and attention

Chronic pain and blood pressure regulation

--In healthy normotensives resting BP and pain sensitivity are inversely related

--Resting BP/acute pain sensitivity relationship is altered in chronic pain patients

--Chronic pain patients have a higher prevalence of HTN

--Greater severity of chronic pain predicted presence of HTN beyond the effects of age, race, and family history of HTN

--This fits with "chronic pain as stressor" theory

"Subgrouping" is becoming more popular in the literature and this presentation was no exception. I found the subgroups presented (these are proposed, not definitive) easier to swallow as the subgrouping is based on physiological differences.

Intact Baroreflex

--Postive resting BP/pain sensitivity relationship
--Baroreflex activation by increased BP suppresses SNS outflow but is NOT analgesic due to:

Dysfunction in descending pain inhibitory pathways normally tirggered by BR activation (via exhaustion, dysregulation, loss of downstream responsiveness)

Low-intensity vagal stimulation triggering DF

Greater central/peripheral sensitizaiton, consequent increased pain sensitivity

--Diminished activation of PAG/RVM or opioid receptor desensitization may lead to reduced recruitment of alpha-2receptors and thereby increase pain sensitivity

Imparied baroreflex

--Negative resting BP/pain sensitivity relationship

--Increased sympathetic outflow due to impaired baroreflex modulation leads to analgesia via:

Increased descending pain inhibition through increased alpha-2 adrenergic activation (PAG via RVM and NRM), coerulospinal noradrenergic and raphe-spinal serotononergic inhibitionof the spina cord

High-intensity vagal stimulation triggering DI

Less extensive central/peripheral sensitization

--Impaired baroreflex similar to hypertensives

--Impaired baroreflex increases cardiovascular risk despite association with reduced pain sensitivity in chronic pain

For those craving conclusions, you'll have to wait for one more post.

Above info. still from OkYung Chung's presentation

[Diane]

For those craving conclusions, you'll have to wait for one more post.
Alrighty then.

[Jon Newman]

Conclusions from Ok.

--Chronic pain patients display imparied post-stress BP recovery and opioid BP modulation, and have a higher prevalence of HTN

--A subset of chronic pain patients may have a major impairment of baroreceptor ability to restrain sympathetic tone leading to HTN and eventual end-organ damage, such as CHF

--Untreated severe chronic pain via sympathetic stimulation and impaired barorefelex could increase risk for MI.

--The combination of sympathtic predominance, vagal withdrawl, and blunted baroreflex sensitivity in some pain patients may represent a treatable mechanistic link between chronic pain and future HTN

--Blood pressure related anti-nociception may be due to descending inhibitory influences from overlapping brainstem sites involved in cardiovascular regulation and pain modulation

--BP increases resulting from acute sensory or emotional excitation may trigger CNS dampening that augments vagal and sympathoinhibitory negative feedback mechanisms to help restore safer BP levels.

--Afferent input from the aortic depressor nerve may exert a tonic inhibitory influence on nociception that is enhanced in hypertensive animals and depressed in chronic pain individuals with lower baroreceptor sensitivity

--Animal studies support central mechanisms affecting both BP and nociception versus peripheral causes depending solely on baroreceptor input.

[Diane]

Before I leave point 2 completely, I'll mention a study done in 1990 by Gargan and Bannister on whiplash, refuting the contention that whiplash pain goes away after settlement of litigation.
(They) reviewed 43 patients who had sustained soft-tissue injuries of the neck, a mean of 10.8 years previously. Of these, only 12% had recovered completely, with residual symptoms intrusive in 28% and severe in 12% Only 48% of the group had been wearing seatbelts; 88% were involved in rear-end collisions. The residual symptoms at follow-up were tabulated (Table 20.1) with neck pain the most common symptom, followed by paraesthesia. Auditory symptoms comprised tinnitus and deafness in equal proportion.

Patients were grouped according to symptom severity: group A (12%) considered they were completely recovered. Group B (48%) had mild symptoms which did not interfere with work or leisure. Group C (28%) complained of intrusive symptoms which necessitated analgesics, orthoses or physiotherapy. Group D (12%) suffered severe problems, had lost their jobs and relied continually on orthoses or analgesics and had undergone repeated medical consultations. Other such studies are quoted in this section. My point in bringing this forward is that I have no reason to think that in most cases were soft tissues of these people handled in any way. This is a book about "Manual Therapy of the Vertebral Column" after all; its whole raison d'etre is to zoom in and justify bone waggling, or handling of the hardest mesoderm of the body. Handling the bones means ignoring the soft tissue that gets squished between the bones and the practitioners hand, including skin, including all the responses the nervous system is trying desperately to signal through its organization of soft tissue behavior.

PT practice patterns work against soft tissues being handled in most cases even today, let alone any way that respects or is informed by information currently available about the nervous system. How are practitioners going to be developed who can learn to do this, given the lack of research fascination with it, and the 4-6 patients/per hour case load scenario? To leave soft tissues and skin out of the treatment picture is simply bad practice, in that they are self regulating if given a chance, in that most of the PNS is within them, and given that right handling would go a long way to prevent their becoming ongoing "nocioceptive drivers." I could go on about this for hours, but I will spare you.

[Jon Newman]

I'm going to try not to bog down the "five questions" thread with info regarding the ANS but the conversation there inspired me to further reduce my ignorance in this area. I dug out our neuroscience text from PT school (co-authored by Eric Kandel, you may have heard of him).

Some basics:

The ANS has three divisions, not two. They consist of the well known parasympathetic and sympathetic systems. However, it also has an enteric division. All three differ in anatomy and organization. Apparently the enteric system can function autonomously but CNS reflexes are usually directing the show. "The enteric system is regulated by an extrinsic innervation that is supplied by the parasympathetic and sympathetic systems....The innervation of the gut by the sympathetic and parasympathetic fibers of the autonomic nervous system provides a second level of control of motility and secretion, but also can override intrinsic enteric activity in situations of emergency or stress."

But back to temperature (from the five questions thread):

"In the system of temperature regulation, the integrator and many controlling elements appear to be located in the hypothalamus....The feedback detector appears to collect information about body temperature from two main sources: peripheral temperature receptors located throughout the body (in the skin, spinal cord, and viscera) and central temperature receptors concentrated in the hypothalamus...The hypothalamic receptors are probably neurons whose firing rate is highly dependent on local temperature, which in turn is determined primarily by the temperature of the blood."

[Diane]

Yay! Basics are good! :)
Thanks for that. I think we should copy that portion of the 5 questions discussion to this thread.

[Jon Newman]

From Prinicples of neural science (3rd ed.), Kandel, Schwartz and Jessell:

Recordings from neurons in the preoptic area and anterior hypothalamus by Tetsuro Hori, Jack Boulant, and their colleagues support the idea that the hypothalamus integrates peripheral and central information relevant to temperature regulation. Units in this region, called warm-sensitive neurons, increase their firing when the local hypothalamic tissue is warmed. Other neurons, called cold-sensitive neurons, respond to local cooling. The warm-sensitive neurons, in addition to responding to local brain warming, are generally excited by warming of the skin or spinal cord and are inhibited by cooling of the skin or spinal cord. The cold-sensitive neurons exhibit the opposite behavior. Thus, these neurons could serve to integrate thermal information from the periphery with that from the brain. Furthermore, many temperature-sensitive neurons also respond to nonthermal stimuli, such as osmolarity, glucose, sex steroids and blood pressure.

[Diane]

This next section of Grieve's article shows some photos of huge spine osteophytes presumed to be sticking forward into the sympathetic chain. 3. Musculoskeletal changes: lesions of trespass
The involvement of preganglionic sympathetic neurons, in lesions of neural trespass or radiculitis in the neighbourhood of intervertebral foramina T1-L2, is virtually inevitable, with consequences which are well understood.

So far as the thoracic spine is concerned, a fairly detailed review of benign and malignant forms of trespass is given in Chapter 29 together with some forms of neuropathy.

Sympathetic neurons may be compromised in other ways, for example (a) by osteophytes (spondylophytes) of intervertebral bodies on the anterior and anterolateral aspects of thoracic and lumbar regions, (b) by arthrotic changes of costovertebral articulations (Nathan 1984) - in the thorax the sympathetic chain lies on the heads of ribs, (c) acquired and/or congenital spinal stenosis (Grieve 1988). Chronic compression of the cauda equina produces not only the vascular features of intermittant claudication but also severe bilateral leg pain, (d) Nathan et al (1982) describe an osseous-fibrous tunnel on the ala of the sacrum, and the considerable variations in size and strength of the lumbosacral ligament which helps to form it. This structure may be a factor in L5 root compression, which can include a sympathetic ramus communicans.

The greater and/or lesser splanchnic nerves, more especially on the right side in the thoracic spine, are often stretched over bony excresences and sometimes incorporated in fibrotic thickenings of connective tissue. They are similar to those in the lumbar spine.

Nathan's (1969) dissections of 344 cadavers revealed predominantly right-sided thoracic osteophytes trespass involving splanchnic nerves in 60.7% of the cases studied.

Nathan (1968) also dissected 390 lumbar sympathetic trunks from 195 adult cadavers. Osteophytes (spondylophytes) were found compressing the sympathetic trunks to some degree in 153 (78.4%) of the cadavers.

The macroscopic changes produced by osteophytic compression were enlargement, angulation and colour changes of the ganglioa, accompanied at times by a sclerotic reaction and adhesion to the surrounding tissue.

The highest incidence was at the L4-L5 interverebral joint, rather more frequently on the right side. The author speculates that symptoms of compression may be expected to appear in the lower limbs and/or pelvic viscera, since features of sympathetic dysfunction are not uncommon in adults and elderly people.

Stewart (1931) described a case of intermittent claudication, in which all the clinical features of early thorombo angiitis obliterans were evident, although radiography did not reveal any arterial sclerotic change. At operation on the left lumbar sympathetic chain, extensive degenerative hypertrophy was revealed extending from L3 to L5. Between L4 and L5 the sympathetic trunk was embedded in a mass of hypertrophic tissue, and was dissected free with great difficulty. Compared with the trunk above this level, the freed section appeared to be contracted. Postoperatively, the left leg was distinctly pinker and warmer than the unoperated right leg.

So. My mind immediately jumps to.. 1. this is horrible, and; 2. how can we try to prevent this happening?
In a seated position, psoas is active. It is attached to the fronts of the vertebral bodies and exerts a pull on them. Could that be helping form osteophytes.. Woolf's law? (Woolfe's law: "Bone accommodates the forces applied to it by altering its amount and distribution of mass.")
So, I'm thinking, less sitting, more prone extension to 1. elongate front of the spine neural tissue (preventively), and; 2. keep the contractile (voluntary or involuntary) stuctures in front of the spine eccentrically lengthenable; (c) maintain slidiness of the lumbar sacral plexuses through the psoases; (d) hopefully keep these big nasty things from growing in the first place and keep the circulatory function to the legs optimal.

Next, section 4. Autonomic nerve involvement in referred pain and other symptoms.

[Diane]

Last section in this chapter.
4. Autonomic nerve involvement in referred pain and other symptoms

Most, if not all, peripheral branches from spinal nerves contain postganglionic sympathetic fibres (Williams et al 1989).

Bourdillon and Day (1987) suggested that the precise role of autonomic nerves in appreciation of pain remains to be clarified; so also do the precise pathways and peripheral destinations of postganglionic sympathetic neurons.

For example Keele and Neil (1971) and others, tabulated the sympathetic supply to the head and neck as follows;
Eye: T1,2; superior cervical, along internal carotid artery
Face: T1,2; superior cervical, along external carotid artery
Skin of head and neck: T1,2; superior cervical, with cervical plexus
Cerebral vessels T1, 2; superior and inferior cervical, along internal carotid and vertebral arteries.

The lowest somatic segmental supply to the upper limb is T3, while the sympathetic supply to the upper limb may be derived as far caudally as T8.

There is experimental evidence in man that pain afferents from the face pass back to upper thoracic segments and thus the spinal cord via the cervical sympathetic chain, i.e., in addition to the multitude of cranial nerve afferent neurons which descend in the spinal tract of the fifth cranial nerve before synapsing in the dorsal region of C1, C2, and C3 segments, as do the somatic afferents of those segments.

Electrical stimulation of the superior cervical sympathetic ganglion can produce pain in the face - precisely the same result is produced when the cervical sympathetic trunk is sectioned and the proximal ends are again stimulated (Smith 1969).

Pain is often referred from spinal segments to body parts which have no nerve connections other than via autonomic nerves. Unnecessary difficulty can arise because of restricted concepts about the cause of clinical features. Referred pain in the head, neck, trunk, and limbs may be thought about in stereotyped ways which might be briefly tabulated as in table 20.3.

Head and neck: Intracranial and extracranial head lesions; temporomandibular joint; upper cervical segments
Upper limb: Lower cervical and uppermost thoracic segments; some diseases of thoracic viscera
Trunk wall: Thoracic and uppermost lumbar segments; some diseases of thoracic and abdominal viscera
Lower limb: Mid/lower lumbar segments; pelvic articulations and hip-joint

We tend to concieve musculoskeletal referred pain in neck, trunk and limb to be a matter of somatic neurons alone, yet readily accept the phenomenon of visceral lesions referring cutaneous pain and tenderness to trunk areas and, in cardiac disease, the left upper limb. Where somatic nerve connections do not exist, e.g. (a) between mid-thoracic segments T345 and the head, and (b) between thoracic segments T4 and caudally and the upper limbs (Ch 29), clinical familiarity and acceptance of pain referred (if that is the right word) in these ways is remarkably thin on the ground, despite the regularity with which manual therapists relieve head pain, and bilateral glove parasthesiae of upper limbs, for example, by simple mobilization of the named thoracic segments.

Our understanding of referred pain is incomplete. Sufficient clinical experience exists to suggest that autonomic nerves may share more actively in the mechanisms underlying its vagaries.

Although much remains to be learnt of the afferent routes of impulses arising in painful pathological conditions of viscera (Willams et al 1989), visceral afferents from the heart are manifestly capable, in cardiac disease, of initiating referred pain down the left arm. Why should this known propensity not be acceptable as a central mechanism in referred musculoskeletal pain too? There are no known visceral aferents from skeletal tissues, but might not the cortical representations of skeletal tissues include the autonomic innervation of blood vessels? Why should not the rich autonomic innervation, and thus cortical representation, have as much to do with patterns of referred somatic pain as somatic nerve representation? This may well explain the notorious untidiness of referred pains, which do not respect (somatic) dermotomes. The question has not yet, to my knowledge, been fully addressed by the many writers on referred musculoskeletal pain.

From Grieve's Conclusion section:
- (re: capasular, ligamentous and tendinous lesions..)"Much is made of friction massage, mobilization, stretching, manipulation, ultrasound, acupuncture, hydrocortisone, cock-up supports, and so on, yet the condition remains notoriously treatment-resistant and the passage of time is usually the one factor which helps many to recover.
- "Bryan et al (1990) investigated peripheral sensory function in reflex sympathetic dystrophy, noting a significant elevation of skin temperature, and a lowering of the pressure pain threshold, in the affected limb. They hypothesize that this leads to further changes in autonomic tone, thus establishing a pathological loop of activity. Sympathetic block abolished pain by allowing peripheral receptors to revert to normal thresholds in the 40 patients of their study. That sympathetic nerve distribution may be an important factor in patterns of referred pain, of musculoskeletal origin, should perhaps be more widely recognized as should the phenomenon of secondary pathology of the soft tissues in areas to which pain is commonly referred from primary axial lesions." (Well, if your belief system is based entirely upon the idea of primary axial lesions, Gregory..:rolleyes: ..otherwise I would concur..)

I plan to bring Butler's POV (from SNS) to this thread, anatomical tidbits from Grey's, and bits of Burnstock.

[Diane]

Ian's link (http://www.in-cites.com/papers/MichaelCaterina.html). This is an interview with Dr. Michael Caterina who talks about his work on 'chili pepper extract' in Nature in 1997, and where it is taking him.
“What we reasoned was that no one had ever identified capsaicin inside the body, so it seemed unlikely that nature had put this channel in our pain-sensing neurons just so we could enjoy eating spicy foods.”

[Diane]

Here is a good sample of Butler's clarity on the matter at hand. From P 84-92:
IMMUNE, ENDOCRINE, MOTOR AND SYMPATHETIC SYSTEMS AS RESPONSE AND BACKGROUND SYSTEMS
INTRODUCTION
The nervous system processes and gives value to any input. Sometimes this value judgement is visibly expressed via the sympathetic (e.g., sweating, redness) or the motor system (spasm, withdrawal, learnt movement patterns). The responses of other systems such as the immune and endocrine systems remain hidden, at least initially, but could be measured. Nervous system response computations are extremely complex, individual and situation specific. They are usually survival driven but often disturbed by novel modern psychosocial demands.

The systems involved often work synergistically. Although considered as response systems, these systems are also closely associated background homeostatic systems, operating at the same time as signalling in the peripheral and central nervous systems.

Systems such as the endocrine, immune and autonomic are foremost protective systems, yet while they can protect and heal, something which requires considerable power, they can also damage, especially in states of maintained stress and pain. Clinical patterns from the activities of these systems are not as obvious as say, peripheral neurogenic pain. Thee is much synergystic activity betweeen systems, and like all pathobiological mechanisms they will always be in action. In extreme states, the systems will become evident, for example the motor system in focal dystonia, the sympathetic nervous system in complex regional pain syndrome and the endocrine and immune system in Cushing's disease and rheumatoid arthritis. Chronic pain probably involves maladaptive responses in all systems.

A useful way to link things together is to look at the integrated actions of the stress response, remembering that pain is probably the ultimate stressor. Stress biology has only recently been associated with the neurobiology of pain (e.g., Gifford 1998; Melzack 1999; Melzack 1999). Such links and use of the clinical consequences are long overdue. Useful general references include Fink (2000), Sapolsky (1994), Lovallo (1997), and Martin (1997).

AUTONOMIC/NEUROENDOCRINE SYSTEM
Pain and stress will activate three key circuits - the hypothalamus-pituitary-adrenal axis (HPA), the sympathoadrenal axis (SA) and the sympathetic neural axis. These are the peripheral limbs of the stress system. The central components are located in the brainstem and hypothalamus. These axes are linked to other brain areas with interests in survival such as the amygdala, multiple cortical areas and the motor system. These three circuits will respond to a variety of signalling including blood borne, sensory, limbic and circadian signals. The circuits will also respond to immune mediated inflammatory moloecules such as tumour necrosis factor alpha and the interleukins 1 and 6.

Pain nearly always acts as a stressor. The activities of these stress systems will also be integrated into the overall CNS processing of pain.

THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS
Paired adrenal glands, perched on top of the kidneys and essential for life are two of the key structures (Fig. 4.5). They have a central medulla and outer cortex. Both areas function in times of stress, but secrete different chemicals; adrenaline and noradrenaline from the medulla (sympathoadrenal axis) and corticosteroids (cortisol) from the cortex. The cortex is part of the HPA axis.

Cortisol secretions are activated by the adrenocorticotrophic hormone (ACTH) secreted into the blood from the anterior pituitary gland. ACTH secretions, matched by cortisol secretions are high in the morning, low in the evening but stimulated by all forms of stress over 24 hours. Forms of stress such as pain, injury, thoughts, feelings, deeds of others, memories and environmental changes are signalled via corticotrophin releasing hormone (CRH) from the hypothalamus to the pituitary gland (Fig 4.5). The actions of CRH are inhibited by blood cortisol levels which are sampled by the hypothalamus. A feedback system is therefore in operation. CRH neurones and noradrenergic neurones innervate and stimulate each other in the brain, thus linking the stress systems (Chrousos 1995).

CORTISOL
It is the adrenal cortex and its secretion cortisol which are particularly critical to life. Almost all tissues of the body have receptors for cortisol, including the brain. Cortisol gets a bad rap as a stress chemical, but it is vital to life. It maintains cardiovascular and metabolic homeostasis, in particular stimulating protein catabolism and glycogen synthesis - vital energy for dealing with emergencies. In addition, cortisol can cross the blood brain barrier and effect brain structures, one result being mood changes including depression. Cortisol can also exert regulatory effects on the inflammatory and immune responses through the inhibition of cytokine action and production. For reviews, see Lovallo (1997), Fink (2000), and Sternberg and Gold (1997).

In an emergency, cortisol shuts down activities not needed for survival and enhances those that are. Hence the inflammatory and immune systems, digestive and reproductive systems are shut down. With the proverbial tiger confrontation, reproduction, digestion, and wound healing are not high priorites - they can wait for later. Energy goes to systems which can help avoid the stress and contribute to survival, such as the cardiovascular system, brain, and muscles, i.e. be smart, think clearly, and perhaps run very fast.

A chronic excess of cortisol as in chronic pain or stress poses problems. Cushing's syndrome (chronic hypercortisolism) is an extremem example. The features include immunosuppression, osteoporosis, cardiovascular disease, depression and insulin resistance (Whitehouse 2000). More subtle cases of tissue degeneration, mood swings, slow tissue healing and susceptability to infection may be noted by clinicians managing patients with chronic pain.

SYMPATHETIC NEURAL AXIS AND SYMPATHETIC ADRENAL AXIS
The HPA axis is closely linked to the sympathetic nervous system (SNS) by links from the hypothalamus to the locus ceruleus, a key sympathetic nervous system control network in the brainstem. The SNS is also mobilized in times of stress, it innervates immune organs as well as nearly every tissue in the body. Stimulation will evoke arousal, fear, and readiness.

The SNS also plays a role in the stress response and body homeostatic function. A well known figure demonstrating the sympathetic nervous system is in figure 4.6. Note that this one is slightly different from most in that it aknowledges that muscles, joints, skin and the connective tissue sheaths of the nervous system have a sympathetic innervation. The sympathetic nervous system output to the entire body iemerges from slinal levels T1 to L3. The paired trunks are continuous, connective tissue sheathed preganglionic structures, and are known to evoke pain if stimulated (Walker and Nulson 1948; Echlin 1949). One preganglionic sympathetic neurone will diverge onto 15 or more postganglionic neurones (Wolf 1941). Its physical health may be of interest to manual therapists (chapter 15). This part of the nervous system is very glandular - noradrenaline can dribble out of numerous varicosities along postganglionic fibres (Chapter 3).

Altough sympathetic responses are ususally widespread (e.g. total limb or body sweating), the sympathetic nervous system has varying layers of control from local organ to the brain (Lovallo and Sollers 2000). Local organ control allows, for example, blood flow adjustments to muscles, another control layer is ganglionic mechanisms which regulate the output of the postganglionic neurones and then the brain and hypothalamus regulate the entire system. The first two respond more to physiological challenges, the brain responds more to psychological stress.

The sympathoadrenal axis is a powerful part of the sympathetic nervous system. Note in figure 4.6 that the adrenal medulla receives a direct sympathetic preganglionic innervation from the spinal cord. This allows secretion of adrenaline and a little noradrenaline directly and rapidly into the bloodstream. This is known as the sympathetic adrenal axis.

ADRENALIN/NORADRENALINE
Mental and physical effects and psychosocial conditions evoke adrenaline and noradrenaline secretions. Mental stress causes more adrenaline secretion whereas physical stress, linked with more physical activity and blood pressure homeostasis evokes more noradrenaline (Lundberg 2000).

Both adrenaline and noradrenaline prepare us for action. They stimulate cardiovascular responses, blood is shunted to the heart, muscles and brain and away from the digestive system and skin. They promote increased levels of glucose and free fatty acids. More oxygen is available, sweating occurs to cool the body and make it slippery. Via its immune organ innervation, these catacholamines can modulate inflammation. Adrealine is immunosuppressive by altering lymphocyte production from the spleen. These are useful secretions for an emergency, but like cortisol, maintained high levels lead to the risk of cardiovascular disease and tissue damage.

Normal or threshold levels of adrenaline do not exist. Levels may double during mild stress such as daily work. Severe stress with emotional demands may cause levels to rise 10 times the resting level for that person. Novel inputs and anticipation markedly raise adrenaline levels (Lunfberg 2000). However an increased level of adrenaline does not necessarily mean pain. While the levels surely contribute, an upregulated sensory system involving inflammation and adrenoreceptors will be necessary for adrenaline and noradrenaline to access the pain system.

SYMPATHETIC NERVOUS SYSTEM AND PAIN
The sympathetic nervous system can contribute to the sensitivity of inflamed tissues and it can also contribute to the sensitivity of damaged nerves. This can be seen spectacularly with increases in pain if adrenaline is injected into patients with nerve injuries such as a neuroma (Chabal et al 1992; Raja et al 1998). However, adrenaline injected into a person with no nerve injury will be painless.

The sympathetic nervous system is essentially a motor system. To cause pain it must somehow activate the afferent system, especially C and A-delta fibres if the CNS is sensitized. Understanding this pain comes back to receptors. Adrenaline itself does not hurt, it needs receptors attached to nocioceptors to contribute to pain or it must contribute to a chemical soup which activates nocioceptors. Therare thus three places where adrenaline may activate the afferent system. These are contributions to inflammatory soup, contributions to and AIGS or influences due to adrenoreceptor upregulation at the DRG. Adrenaline can act as a central excitatory neurotransmitter, thus it may contribute to the magnification of afferent input. There are more details in chapter 3. Review also figure 3.9.

The stress chemicals such as noradrenaline and cortisol could also contribute to input via destructive effects on tissues. Persistent high level bathing by cortisol and catecholamines appears to have a deleterious effect on connective tissues (Oxlund and Manthorpe 1982; Curwin et al. 1988; Eyre 1990). Noradrenaline pathways in the brain are also closely linked to negative emotional states.

THE PARASYMPATHETIC NERVOUS SYSTEM
Often forgotten with the excitement of the sympathetic nervous system is the parasympathetic nervous system. "Flight and fight" has reminded generations of students about the role of the sympathetic nervous system. The catch cry of the parasympathetic nervous system - "rest and digest" was also proposed by Cannon (Kandel et al 1995), and is just as important for students and patients to understand. Usually these two systems balance each other. The parasympathetic nervous system is more operational at rest when it repairs and heals the tissue traumas of the day.

It may be worthwhile telling patients about this healing and helping system, particularly when talking about sleep health and the need for some patients to introduce relaxation as a coping strategy. To be continued. Next, MOTOR SYSTEM AS AN OUTPUT SYSTEM.

I would beg to quibble slightly with Butler about the effects of sympathetic shunting in the brain. He says blood flow is increased to the brain. I would want to ask, which parts? My contention is that blood flow likely increases to the parts that decode vision, equilibrium, motor planning, rage etc.. all the non-conscious mechanisms for enhancing escape. I seriously doubt this involves any sort of thinking in the usual sense of the word, in other words, if a tiger is going to bite you, you aren't going to bother to put a finger to your head to ponder in that moment if it is a Siberian tiger or a Sumatran tiger, or work out the evolutionary tree and where they might have diverged, or stop to chat to your child about the difference in a moment of verbal social grooming. Not really. Chances are the danger would strike one mute except for perhaps a howl issuing from some preverbal part of the more non-conscious brain. So my understanding is that blood flow or at least glucose uptake is actually decreased to the frontals in lots of places and increased elsewhere. Aftrer all, the brain is not monolithic, and lots of the planning/escape centres are evolutionarily much older than the "human" bits.

[Diane]

MOTOR SYSTEM AS AN OUTPUT SYSTEM
Muscles can be inflamed, acidic and weak and hence be potent sites of high threshold input into the CNS. There are secondary effects of damaged muscle also, for example joint instability or a change of the container tissue around a peripheral nerve, all of which could contribute to primary or secondary hyperalgesia.

The motor system can also be conceptualized as a response system. Motor responses to pain and stress include weakness, spasm, changes in facial expressions and tone of voice, muscle imbalances, loss of quality and range of movement, loss of variety of movement selections etc. To some degree these changes are a product of the physical health of the muscles, but they are also products of central processing and are essentially coping mechanisms. Like the increased cortisol in acute stress, some spasm and muscle tension (e.g., Knost et al 1999), even a change in tone of voice are useful in acute pain and injury if it enables optimal management. If they persist then these once useful behaviors become maladaptive and destructive to outcome.

A hyperactive sensory system will have repercussions for the motor system (Woolf 1984) as well as the other output systems. Like the sympathetic nervous system, there are local responses such as spasm and ill-health of collagen. There are also observable changes in patterns of gross movement and postures as people cope. These are often conceptualized as muscle imbalance syndromes. The decreased movement options available and the learned habits of the chronic pain sufferer may lead to deconditioning.

Muscles will react to thoughts. The cortical activity which occurs at the thought of a movement is similar to the cortical activity when the movement occurs (Lotze et al 1999). In an experimental situation patients with chronic low back pain who discussed pain episodes had elevated EMG activity compared to those exposed to neutral stimuli (Flor et al 1992). Powerful psychophysiological influences on motor behavior include fear of movement, fear of reinjury, and fear of pain (for recent reviews see Vlaeyen et al 1995; Crombez et al 1999; Vlaeyen and Crombez 1999).

The straight leg raise (SLR) is one of the key neurodynamic tests (Chapter 11). McCracken et al. (1993) showed that anxiety related to pain was a predictor of pain level and range of SLR movement in chronic low back pain patients.

IMMUNE SYSTEM
BASIC APPARATUS
The days of considering the immune system as a separate system to the nervous system are gone and there are now well defined multilevel and reciprocal links between the immune system and the nervous system. For reviews of the nervous system and pain see Watkins (2000), Watkins and Maier (1999), Black (1995) and Sternberg and Gold (1997).

The immune system comprises organs (bone marrow, thymus, lymph nodes, and spleen) and various cells (T cells, B cells, natural killer cells, macrophages, and neutrophils). It also comprises messenger molecules known as the cytokines, which allow communication between cells. Sternberg and Gold (1997) note that the immune and nervous systems are quite similar in that they possess sensory elements which recieve information from the body and the environment, and they possess motor elements to carry out responses. The cytokines fulfil that role and are of particular interest here.

CYTOKINES
Cytokines are produced in response to various physical and emotional stressors. They have a critical role in infection control and can powerfully contribute to inflammation and pain. Some cytokines are anti-inflammatory and some are pro-inflammatory, making something of a balance. The identified pro-inflammatory cytokines are interleukin-1 (IL-1), interleukin-2 (IL-2), and Tumour Necrosis Factor Alpha (TNF alpha), called TNF alpha because it will cause a haemorrhaging necrosis of tumours if injected into animals. It's apparently powerful stuff. The anti-inflammatory ones include IL-4, IL-10 and IL-13. If a human is injected with IL-1, fever, headache, joint and muscle pain will ensue (Dinarello 1999). IL-1 also stimulates prostaglandin and phospholipase A2 synthesis as part of a contribution to the chemical cascade of inflammation. For reviews see Marshall (2000) and Watkins (1999).
The immune system is powerfully regulated by the peripheral and central nervous systems, although this signalling is not all one way. Any CNS activation via physical and psychological stressors may result in immunity changes (Ligier and Sternberg 2000). Activation of the HPA axis and the sympathetic nervous system axes will effect immunity primarily by release of cortisol. See figure 4.7. The sympathetic nervous system also modulates the immune system through its innervation of the immune organs such as the spleen and lymph nodes. Peripheral nerve responses such as substance P (Dickerson et al. 1998) will activate pro-inflammatory cytokines.

The proinflammatory cytokines IL-1, IL-2 and TNF alpha can also signal the nervous system in a number of ways. Cytokine signalling can occur through its stimulatory effects on the inflammatory soup and in damaged peripheral nerve as discussed in chapter 3. Cytokines have an influence in the brain also, but these large proteins have some difficulty crossing the bloood-brain barrier. They require a leaky section to pass. Another mode of signalling is thought to involve sensory paraganglia attached to the vagus nerve (Maier et al 1998; Watkins and Maier 2000). The vagus nerve terinates in the nucleus tractius solitarius which has links to many areas such as the hippocampus and hypothalamus. Glia in the spinal cord and brain will respond to immune signalling by synthesizing and releasing IL-1 and thus stimulating the release of further neuroactive substances such as nitric oxide, NGF and excitatory amino acids such as glutamate. Interleukin 1 can potentiate secretion of corticotrophin releasing factor and thus a stress response. (Watkins et al. 1994; Watkins and Maier 2000). The brain is perghaps the most prolific endocrine organ in the body (Sternberg and Gold 1997).

THOUGHTS FOR CLINICIANS
Much is made of our stress response systems having to function in the age of computers, bureaucracy, new diseases, pollution and job stress, all with a design based on the needs of many thousands of years ago. As Nesse and Young (2000) suggest, we may have forgotten that the ancestral physical stresses of no police, no food resources, no laws, rampant diseases and predators were/are also extremely powerful.

The majority of research articles about pain mechanisms state that their hope is that the findings may lead to improved pharmacological inteventions. Only a few look at other options and realize that the non-drug management potential is also increasing and the side effects may be less. In addition to improving tissue health, cardiovascular fitness and applying various movement enhancement strategies, there are a number of psychosocial variables which can be manipulated by movement based therapists as a management strategy or to enhance a physical strategy. For example, optimism, motivation, coping methods, an understanding of the meaning of pain, and social support will all, to some degree, protect against the psychological, cardiovascular, endocrine, and immune effects of stress. The reasoning models proposed in chapters 6 and 7 should allow integration of all pain mechanisms. In figure 4.8, there is a summary of the pain mechanisms. This links the peripheral mechanisms (chapter 3) with the central and response mechanisms in this chapter. The part about vagus, usually thought of as a parasymathetic nervous system structure, being part of the immune system function is interesting. See attached thumbnails. The flow chart with rectangles is great. But I have wandered away from the autonomics as such. I'll wander back in again.. topical issues in pain, Gray's, etc.

[nari]

These might be helpful - the study that demonstrated the vagus's role in the immune system.
http://www.northshorelij.com/body.cfm?id=204&action=detail&ref=616

http://nature.com/nature/journal/v241/n6921/full/421328a.html

Nari

[Diane]

Thanks Nari. Great!
The link to nature.com only goes to an index of articles, not THE article.. if you have it, could you attach the actual article or send it by email so we could put it in sounds of silence (if it's copyright, which I'm sure is the problem)?

[nari]

That's weird. I typed in the URL of the article - don't know what happened there. Will try again.

Nari

PS I could not work it out, so have just sent the article to you.
It is surprising that Nature allows access to full articles - usually there is none.

[Diane]

http://www.nature.com/nature/journal/v421/n6921/full/421328a.html
Inflammation: A nervous connection

Claude Libert
Top of page
Abstract

The molecular details of a connection between the nervous system and the inflammatory response to disease have been uncovered. This suggests new avenues of research into controlling excessive inflammation.

Sepsis is a complex, exaggerated and chaotic version of the usually well-organized inflammatory arm of our immune defences, and kills over 175,000 people each year in the United States alone1. Although a great deal of time and effort has been spent researching septic shock, it remains difficult to understand and treat. One promising lead was provided two years ago, when it was discovered that there is a connection between inflammation and the involuntary nervous system. The details of this link have, however, been unclear — until now. Writing on page 384 of this issue, Kevin Tracey and colleagues2 describe how they identified a receptor protein that is stimulated by the nervous system and which in turn inhibits a key molecular mediator of inflammation and septic shock. This receptor might make a good target for future drugs to treat sepsis.

Inflammation has several roles in the body, one of which is to contribute to the immune system's ability to fight off intruding microorganisms. For instance, molecules that are produced during the inflammatory response increase blood flow to infected areas, or help to recruit immune cells. One way in which inflammation is triggered is in response to lipopolysaccharides — components of the cell walls of many bacteria — which activate the immune system's macrophages. These cells in turn release 'alarm' molecules, namely cytokines, some of which have powerful pro-inflammatory properties. Tumour-necrosis factor (TNF) is one such molecule. This protein can affect nearly all cell types, and has a range of biological activities. For instance, it induces the expression of a large number of genes that encode essential inflammatory molecules (such as other cytokines; enzymes that help to break down the barriers between cells, allowing the migration of immune cells; and adhesion molecules that again enhance immune-cell migration)3, 4.

As long as TNF production remains confined to the site of infection, the inflammatory response is clearly beneficial. But once bacteria, and consequently TNF, invade the systemic blood circulation, blood 'poisoning' and sepsis can develop quickly. Furthermore, TNF has been found to be a central mediator of chronic inflammatory disorders such as rheumatoid arthritis and Crohn's disease. So there is much interest in learning how to control the production, release and activity of TNF. Several means of doing so have been developed (Fig. 1), and have seen some success in treating certain inflammatory disorders5. For instance, there are drugs that inhibit the transcription of the TNF-encoding gene into messenger RNA, the translation of the mRNA into protein, or the release of the TNF protein. There are also antibodies and soluble receptors that bind to and block TNF once it has been released. But, although the value of these approaches is beyond doubt, they all take time to work — and time is usually short when treating patients with sepsis.
Figure 1: The inflammatory response to microorganisms, and ways of controlling it.
Figure 1 : The inflammatory response to microorganisms, and ways of controlling it. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Clockwise from lower right: many bacteria contain lipopolysaccharide in their cell walls, which stimulates macrophages. These immune cells then make and release various cytokine ('alarm') molecules, including tumour-necrosis factor (TNF) and interleukin-1. But too much TNF in the blood can be harmful, leading to excessive inflammation and septic shock. Several drugs (orange boxes) inhibit steps in TNF synthesis. In addition, Tracey and colleagues have found that when the vagus nerve detects interleukin-1 (left), it releases acetylcholine (right), which binds to the alpha7 receptor2 on macrophages and inhibits cytokine production. This suggests possible new ways of controlling inflammation: through electrically stimulating the vagus nerve, by acupuncture, or with the use of nicotine (which mimics acetylcholine).
High resolution image and legend (45K)

Tracey's research team has been studying TNF since this protein was discovered (see, for instance, ref. 6). Recently, Tracey's group described another level of control of TNF synthesis — namely by means of the vagus nerve7 — thereby providing a new and exciting link between the involuntary nervous system and inflammation. This 'parasympathetic' nerve emanates from the cranium and innervates all major organs in a subconscious way. It is finely branched and is composed of both sensory (input) and motor (output) fibres. This is of relevance because it means that the vagus nerve can on the one hand sense continuing inflammation (presumably by detecting cytokines through receptors on the nerve surface), and on the other hand suppress it. This suppression is efficient and, above all, a good deal faster than the mechanisms mentioned above. Tracey's group found7 that, after injecting lipopolysaccharides into rats, electrically stimulating the vagus nerve prevented both the release of TNF from macrophages, and death. Conversely, surgically severing the nerve not only removed this protection but also sensitized the animals to lipopolysaccharide.

But how does the vagus nerve have this effect on macrophages? It was already known that, after this nerve is stimulated, its endings release the neurotransmitter molecule acetylcholine with lightning speed. Macrophages express acetylcholine receptors known as nicotinic receptors, and respond to the released acetylcholine (or the acetylcholine-mimicking nicotine) by suppressing TNF release. But the precise identity of the nicotinic receptors on macrophages was not known. From a therapeutic point of view, this is clearly important to know. It's also very difficult to find out, as the receptors are pentamers containing different combinations of a possible 16 monomers.

In their latest paper, Tracey and colleagues2 pin down the relevant nicotinic acetylcholine receptor: it is one comprising five copies of the monomer alpha7. They started by using alpha-bungarotoxin, a molecule that binds to just a subset of receptor monomers, to show that macrophages express the alpha7 subunit. When the authors blocked the expression of this protein, acetylcholine and nicotine were no longer able to prevent the release of TNF — data that the authors confirmed by studying alpha7-deficient mice. In fact, such mutant mice displayed an exaggerated response to lipopolysaccharide in terms of their production of the cytokines TNF, interleukin-1 and interleukin-6. Finally, in a technical tour de force, Tracey and colleagues showed that electrically stimulating the vagus nerve of alpha7-deficient mice no longer afforded protection against lipopolysaccharide (in contrast to the situation in wild-type mice).

These findings2 could have therapeutic implications. The discovery of the connection between the involuntary nervous system and inflammation had already yielded new ideas about treating inflammatory disorders such as sepsis: for instance, a small compound has been developed that can trigger the vagus nerve in rats, thereby reducing inflammation8. Looking to the future, it would be interesting to stimulate the vagus nerve electrically in people — as is currently done in thousands of epilepsy patients, showing that the procedure is safe and feasible — and to study the effect on inflammation. More specifically, the new findings suggest that molecules that stimulate the alpha7 subunit would also be worth developing.

On a different note, nicotine has been found to have powerful immunosuppressive and inflammation-suppressing effects. Of course, the health risks associated with smoking are immense. Yet epidemiological studies indicate that nicotine protects against several inflammatory diseases, such as ulcerative colitis, Parkinson's disease and even Alzheimer's disease. It can also reduce fever and protect against otherwise lethal infection with the influenza virus9. The demonstration2 that nicotine binds to the alpha7 subunit on macrophages fleshes out the details of how nicotine produces such effects.

The data also make me reconsider the possibilities and molecular biology of 'alternative' medicine. Pavlovian-type conditioning, hypnosis and meditation are well known (since the beginning of the twentieth century in some cases) to reduce inflammation10. It might be worth finding out whether these effects, as well as the reported beneficial effects of prayer and acupuncture on inflammation (the last of which is known to depend on acetylcholine)11, 12, are mediated by the vagus nerve and the alpha7 subunit.

Thanks Nari!:thumbs_up
Anyone else, please report if the link doesn't work.. it works fine for me now. Thanks.)

[Diane]

Weirdest thing.. the site won't let me go back in to edit my last post. Oh well..
Sepsis is a complex, exaggerated and chaotic version of the usually well-organized inflammatory arm of our immune defences, and kills over 175,000 people each year in the United States alone1. Although a great deal of time and effort has been spent researching septic shock, it remains difficult to understand and treat.

I wonder if this isn't the organism's way of trying to commit suicide? Like apoptosis, only not at a single-cell level, rather at a multicell level.. We being human, of course, we hate to let go.

[emad]

Hope this good link :

http://education.yahoo.com/reference/gray/

Regards
Emad

[Diane]

p. 909: The peripheral nervous system comprises the cranial and spinal nerves and the peripheral part of the autonomic nervous system (see p. 1292) including the enteric nervous system (composed of plexuses of nerve fibres and cell bodies in the wall of the alimentary tract). The peripheral nervous system is composed of the axons of motor neurons situated inside the central nervous system, and the cell bodies and processes of neurons grouped together as ganglia (swellings). Sensory ganglion cells in posterior (dorsal) roots give off both centrally and peripherally directed processes, and do not have synapses on their cell bodies, whilst ganglionic neurons of the autonomic nervous system receive synaptic contacts from various sources. The cell bodies situated in peripheral ganglia are all derived embryonically by migration from the neural crest. (p. 147).

On p 146 is just a reminder of what neural crest is about.
On P. 1292 is the real deal on the ANS. Get ready, there are pages and pages of info here to bring on:
GENERAL ORGANIZATION:
The autonomic nervous system posesses both central and peripheral components, the latter being concerned with the innervation of the viscera, glands, blood vessels and non-striated (smooth) muscle. It therefore forms the visceral (splanchnic) component of the nervous system. The term 'autonomic' is a convenient rather than appropriate title. The autonomy of this part of the nervous system is illusory, since it is intimately responsive to changes in somatic activities. While its connections with somatic elements are not always structurally clear, the functional evidence for visceral reflexes stimulated by somatic events are abundant. (For general information consult Langley 1921, Kuntz 1953; Mitchell 1953, 1956; Pick 1970; Gabella 1976; Bjorkland et al 1988; Bannister & Mathias 1992; Burnstock 1992-95.)

Visceral efferent paths differ from their somatic equivalents in being interrupted by peripheral synapses, at least two neurons being interposed between the central nervous connections and visceral effectors (8.392). The somata of the primary neurons are in the visceral efferent nuclei of cranial nerves and in the spinal lateral grey columns; their axons, variably but usually finely myelinated, traverse the cranial and spinal nerves to the peripheral ganglia, where they synapse with the dendrites of somata of secondary neurons. Axons of secondary, effector neurons are usually non-myelinated and supply non-striated muscle or glandular cells. These nerve fibres are also found close to adipocytes, mast cells, melanophores, interstitial cells, autonomic ganglia and motor end plates. There are therefore in peripheral efferent pathways preganglionic and postganglionic neurons, the latter being more numerous; one preganglionic neuron may synapse with 15-20 postganglionic neurons, permitting the wide diffusion of many autonomic effects. This disproportion between preganglionic and postganglionic neurons is said to be greater in the sympathetic than in parasympathetic parts of the autonomic nervous system. (In an investigation into human superior cervical ganglia, a ratio of preganglionic to postganglionic fibres of 1 to 196 was claimed; Ebbesson 1968.) Terminations of postganglionic neurons are described on page 959 and below. For the structure of sympathetic ganglia and details of other neuronal types, including interneurons, see page 1298 et seq.

Visceral afferent paths resemble somatic afferent paths; the cells of origin of their peripheral fibres are unipolar neurons in cranial and dorsal root ganglia. Peripheral processes are distributed through autonomic ganglia or plexuses, or possibly through somatic nerves, without interruption. Their central processes (axons) accompany the somatic afferent fibres through dorsal spinal roots to the CNS (P. 1298).

The autonomic nervous system can be divided into three major parts, parasympathetic, sympathetic, and enteric, which differ in structure and function. The broad anatomical organization of these subdivisions was summarized by Langley in 1921 and has been more or less retained since that time. Parasympathetic preganglionic efferent fibres emerge through certain cranial and sacral spinal nerves as a craniosacral outflow, while sympathetic preganglionic efferent fibres emerge through thoracic and upper lumbar spinal nerves as a thoracolumbar outflow. The somata of parasympathetic postganglionic neurons are peripheral, sited distant from the CNS either in discrete ganglia near to the structures innervated or often dispersed in the walls of the viscera. The somata of sympathetic postganglionic neurons are located mostly in ganglia of the sympathetic trunk or ganglia in more peripheral plexuses but they are almost always nearer to the spinal cord than to the effectors innervated, an exception being some of those innervating pelvic viscera. The enteric nervous system is comprised of ganglionated plexuses localized in the wall of the gastrointestinal tract (p 1749). It contains reflex pathways through which the contractions of the muscular coats of the alimebtary tract, the secretion of gastric acid, intestinal transport of water and electrolytes, mucosal blood flow and other functions are controlled. There are complex interactions between the enteric nervous system and extrinsic parasympathetic, sympathetic and sensory-motor nerves.
The figure 8.392 is a version of the common one of the side view of the spine and all the levels of ganglia with outflow to the organs, eye, etc.etc.
Next, mechanism of transmission. So much juicy stuff in this section.

[Diane]

P. 1294 Gray's: MECHANISM OF TRANSMISSION
It has been considered in the past that physiologically the parasympathetic and sympathetic systems differed in that parasympathetic reactions are generally localized, whereas sympathetic reactions are mass responses. However, even though widespread activation of the sympathetic nervous system may occur, for example in association with fear or rage, it is now recognized that the sympathetic nervous system is also capable of discrete activation, and many different patterns of activation of sympathetic nerves throughout the body occur in response to a wide variety of stimuli.

Parasympathetic activity results in cardiac slowing and an increase in intestinal glandular and peristaltic activities, which may be considered to conserve body energy stores. Sympathetic activity results, for example, in the general constriction of cutaneous arteries (increasing blood supply to the heart, muscles and brain), cardiac acceleration, increase in blood pressure, contraction of sphincters and depression of peristalsis, all of which mobilize body energy stores for dealing with increased activity (MacDonald 1992). I see Gray's uses the term "brain" in general. Hmmnn.
This paragraph sums up the sym/parasym behavior contrast in a nutshell however; skin is drained while the muscle system is fed, when sympathetics are engaged/needed.

For many years the idea of antagonistic, parasympathetic cholenergic and sympathetic adrenergic control of most organs in visceral and cardiovascular systems formed the working basis of all studies. However, major advances have been made since the early 1960s that make it necessary to revise this concept of the mechanism of autonomic transmission. These advances include:(I'm writing out a short list of bullets that isn't in the book, outside the quote box. See further down for detailed list quoted as written):

NANC nerves
Cotransmission
Neuromodulation
Sensory-motor nerves
Intrinsic circuitry
Autonomic neuromuscular junction
Plasticity

NANC nerves. The discovery of non-adrenergic, non-cholinergic (NANC) nerves and the recognition of a multiplicity of neurotransmitter substances in autonomic nerves. Adenosine 5'-triphosphate (ATP) satisfied the criteria as a neurotransmitter in many of these NANC nerves and they were termed 'purinergic' (Burnstock 1972). Subsequently, it became clear that many other neuroactive substances, including many peptides, were present in autonomic nerves. Nitric oxide (NO) or a NO-related compound has recently been showqn to play an important role as a primary messenger in transmitting information from nerves to smooth muscles in specific tissues (Bredt et al 1990; Rand 1992). The list of proposed neurotransmitters and neuromodulators in the autonomic nervous system thus includes monamines, purines, amino acids, a variety of peptides, and NO (P. 935 and Table8.1; Burnstock 1986).

Co-transmission. The concept of cotransmission that proposes that most, if not all, nerves release more than one transmitter (Burnstock 1976, 1990; Hokfelt et al 1986; Kupfermann 1991) and the 'chemical coding' of these nerves to establish the combinations of neurotransmitters contained in individual neurons whose projection and central connections are known. The principal neurotransmitters in most sympathetic nerves are ATP and neuropeptide Y (NPY), although NPY often acts as a neuromodulator. In parasympathetic nerves the principal cotransmitters are actetycholine (ACh), and VIP, with subpopulations utilizing ATP and/or NO. In most sensory-motor nerves (P 968), the neurotransmitters are substance P (SP) and calcitonin gene-related peptide (CGRP), with some utilizing ATP. Other neurotransmitters/neuromodulators are also sometimes colocalized with the principal transmitters in autonomic nerves (8.393). Although there are many different transmitter substances in the gut, most are involved in neurotransmission or neuromodulation at the ganglion level or may be trophic factors. The number involved in neuromuscular transmission is more limited. Enteric NANC inhibitory nerves utilize, probably as cotransmitters, ATP, VIP, and NO whereas enteric excitatory nerves utilize ACh and SP. I'll bring a thumbnail of this diagram. It shows the breakdown of what transmitters are found with which type of nerve.

Neuromodulation. The concept of neuromodulation, where locally released agents can alter neurotransmission either by prejunctional modulation of the amount of transmitter released or by postjunctional modulation of the time course or intensity of action of the transmitter. The wide and variable cleft characteristic of autonomic neuroeffector junctions makes them particularly amenable to the mechanisms of neural control mentioned above. There are many different ways in which cotransmitters and neuromodulators interact to effect neurotransmission including:

- Autoinhibition, by which a transmitter, in addition to its postjunctional effects, modifies its own release, often inhibiting it which may in turn effect the release of cotransmitters;
- Cross-talk, by which a neuromodulator may act on closely juxtaposed terminals;
- Synergism, by which each of two transmitters, either from different nerve terminals or cotransmitters, have the same postjunctional effect so that there is a reinforcement of their individual effects;
- Opposite actions, which may result from a transmitter having opposite actions in different effector cells, or the response may depend on the tone of the effector cell;
- Prolongation of effect, by which a neuromodulator may act on degradative enzymes, for example peptidases responsible for removal of neuropeptides from the junctional cleft, to prolong the time course of their effect;
-Trophic effects, by which a neurotransmitter may effect theee expression of another transmitter or receptor within a population of neurons (for example in ganglia) at the level of gene transcription.
All these mechanisms of control of neurotransmission reflect the versitility of the ANS.

Sensory-motor nerves. The importance of sensory-motor nerve regulation in many organs is recognized (p. 667). These afferent nerves run in motor fibres with their cell bodies in cranial and dorsal root ganglia. While many such nerves are purely sensory, certain primary afferent nerve fibres have been termed sensory-motor since they release transmitter from their peripheral endings during the axon reflex and have a motor rather than a sensory role (see p 965) (Maggi 1991). For many years the status of the sensory nerve in the autonomic nervous system has been debated but now it is recognized that sensory-motor nerve regulation is an important feature of autonomic control in the gut, lungs, heart, ganglia, and blood vessels.

Intrinsic circuitry. Recognition that many intrinsic ganglia contain integrative circuits and are capable of sustaining and modulating sophisticated local activities. Although the ability of the enteric nervous system to sustain local reflex activity independent of the CNS has been recognized for many years (Kosterlitz 1968), it has been generally assumed that the intrinsic ganglia in peripheral organs such as the heart, airways, and bladder consisted of parasympathetic neurons that provided simple nicotinic relay stations. The high degree of electrophysiological specialization displayed by these intrinsic neurons suggests that they may act as sites of integration and/or modulation of the input from extrinsic nerves or permit some local control of aspects of visceral function by local reflex mechanisms (Allen & Burnstock 1990). Thus, since intrinsic neurons survive following section of the extrinsic sympathetic and parasympathetic nerves, transplanted organs are not denervated. Intrinsic neurons are derived from the neural crest, independent of sympathetic and parasympathetic nerves. Various combinations of transmitters have been shown to coexist in subpopulations of intrinsic neurons in atria, bladder and trachea and in the chemical coding in the enteric nervous system has been studied extensively (Furness & Costa 1987, p 1749).

Autonomic neuromuscular junction. Recognition that the autonomic neuromuscular junction differs in several important ways from the skeletal neuromuscular junction and from the synapses in the CNS and PNS (see Burnstock 1981). There is no fixed junction with well defined pre- and postjunctional specializations. Unmyelinated, highly branched, postganglionic autonomic nerve fibres reaching the effector smooth muscle become beaded or varicose (8.394). These varicosities are not static but are able to move along axons, consistent with the lack of postjunctional specialization. They are packed with mitochondria and vesicles containing neurotransmitters. The distance of the cleft between the variscosity and smooth muscle varies considerably depending on the tissue, from 20 nm in densely innervated structures such as the vas deferens to 1-2 um in large elastic arteries. Neurotransmitter is released en passage from variscosities during conduction of an impulse along an autonomic axon; however, it is possible that a given impulse will evoke release from only some of the variscosities that it encounters.

Another important feature of the autonomic neuromuscular junction is that, unlike striated muscle, the effector tissue is a muscle bundle rather than a single cell and low resistance pathways between individual muscle cells allow electronic coupling and spread of activity within the effector bundle. These are represented by areas of close apposition between the plasma membranes of adjacent cells which can be identified under the electron microscope as gap junctions or nexuses (p 958). Gap junctions vary in size from punctate junctions to junctional areas of more than 1 um in diameter. Little is known abou