Autonomic state in pain and correction

[Diane]

Butler, "Sensitive Nervous System", on "response" and "background systems"

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]

Butler (cont.)

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.cf...detail&ref=616

http://nature.com/nature/journal/v24...l/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...l/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]

From Gray's

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]

MECHANISM OF TRANSMISSION

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 about the quantity and arrangement of gap junctions in effector bundles relative to the density of autonomic innervation. Thuis, within an effector muscle bundle only a certain percentage of cells are directly innervated, the remainder being coupled to these cells via gap junctions (Hillarp 1959; Burnstock 1986).

Plasticity. Recognition of the plasticity of the ANS, not only in normal development and ageing, but also in changes in the expression of neurotransmitters and receptors in the mature adult in response to hormones and growth factors following trauma, surgery, chronic drug treatment, and in a variety of disease situations (Burnstock 1990, p 959).

Figure 8.394 is a depiction of an autonomic neuron with variscosities.

Next, more on the plasticity of the ANS.

[Diane]

PLASTICITY OF THE ANS

P 1295 Gray's:

PLASTICITY OF THE AUTONOMIC NERVOUS SYSTEM
Autonomic neuroeffector systems show a high degree of plasticity, even in mature adult animals (see Black et al 1988; Burnstock 1990; Hendry & Hill 1992). Changes in expression of transmitters and cotransmitters in autonomic nerves occur during developing and ageing, after chronic exposure to drugs, in a number of disease situations and in nerves that remain following trauma or surgery. Several different types of adaptive mechanisms appear to override the normal genetic programming of transmitter and receptor expression, for example alteraons in availability to growth factors, levels of nerve activity, removal of inhibitory innervation and hormonal changes. Neurotrophins synthesized by target smooth muscle, of which nerve growth factor is the best known example (Levi-Montalcini & Angelletti 1968; Thoenen 1991, p 919), have long been recognized to have trophic influences on sympathetic and sensory nerves of the autonomic nervous system. There is growing evidence that several neurotransmitters, in particular the neuropeptides, which are involved in short-term communication between excitable cells, also have long-term trophic actions on autonomic nerves (Pincus et al 1992). Autonomic neurons are thus continually under the influence of the molecules of their environment, allowing for a considerable degree of plasticity following injury (Hendry & Hill 1992).

Degeneration in the autonomic nervous system resembles that in cerebrospinal nerves. Some evidence suggests that the rate of degeneration differs in different regions or different types of fibre. Regeneration of preganglionic fibres may vary with the site of lesion and, in postganglionic neurons, regeneration may be followed by reinnervation from neighbouring intact nerve fibres. As far as experimental evidence goes, the integrity of Schwann cell sheaths is essential in the regeneration of autonomic nerve fibres (Evans & Murray 1954; Kapeller & Mayor 1967; Williams 1971; King & Thomas 1971; Landon 1976). Some observations suggest that proximity of myelinated fibres is necessary for regeneration in non-myelinated fibres (Evans & Murray 1954; Williams 1971; Lisney 1989; consult Fawcett & Keynes 1990). It is pertinent to mention earlier experiments in which large experimental gaps in the sympathetic trunk, in monkeys and other mammals, have been filled by the growth of fibres, pre- or postganglionic (Tower & Richter 1931; Haxton 1954). Functional recoveries may sometimes be explained by incomplete interruption of the sympathetic supply or by alternative routes being overlooked.

Next, surgical anatomy.

[Diane]

Surgical anatomy

P 1296 Gray's:

Surgical anatomy. Various autonomic nervous structures are divided or removed in treating several pathological conditions. In operations on the efferent sympatetic paths, ganglia on the sympathetic trunk are removed or preganglionic fibres cut, rather than postganglionic fibres, since the latter may regenerate. For example, the arteries of limbs may be denervated to alleviate vascular spasm (Raynaud's disease) and the parts removed are as described above (pp. 1258, 1302). In the treatment of hypertension, more extensive sympathectomy has been performed, involving bilateral removal of the sympathetic trunks from the eighth thoracic to the first lumbar ganglia, including the greater and lesser thoracic splanchnic nerves. Sympathectomy is also performed to relieve pain, for example in severe angina pectoris (p. 1311). Division of the superior hypogastric plexus (presacral neurectomy) does not relieve all pain in disease of the pelvic organs, because many pain fibres traverse the pelvic splanchnic nerves. However uterine pain fibres pass in sympathetic nerves via the superior hypogastric plexus so that this division does relieve dysmenorrhoea. In males resection of the superior hypogastric plexus leads to loss of ejaculation and sterility, due to interruption of the sympathetic paths to the seminal vesicles, deferent ducts and prostate. The routes of these nerves between the sympathetic ganglia and the superior hypogastric plexus are uncertain and may vary; but in some individuals an outflow from the first lumbar and possibly the twelfth thoracic ganglia is concerned and in others fibres from the third lumbar ganglion (White et al 1952).

Yikes.

Next, Parasympathetic NS. Nice big section, a full page. After that, the Sympathetic NS has its very own section, twelve pages long! We'll be lovingly delving into every ganglion known to humanity, if you can stick with this.

[Diane]

PARASYMPATHETIC NERVOUS SYSTEM

P 1297 Gray's:

PARASYMPATHETIC NERVOUS SYSTEM
EFFERENT PATHWAYS
Preganglionic parasympathetic axons are myelinated and occur in the oculomotor, facial, glossopharyngeal, vagal, and accessory cranial nerves and in the second to fourth sacral spinal nerves. In the cranial part of the parasympathetic system there are four small peripheral ganglia: cilliary (p 1228), pterygopalatine (p. 1235), submandibular (p. 1247) and otic (p. 1250), all described in this account with their cranial nerves. These are soley efferent parasympathetic ganglia, unlike the trigeminal, facial, glossopharyngeal and vagal ganglia, all of which are concerned exclusively with afferent impulses and contain the somata of sensory neurons only. The cranial parasympathetic ganglia are traversed by afferent fibres, postganglionic sympathetic fibres and, in the otic, even by branchial efferent fibres, but none of these are interrupted in the ganglia. Postganglonic parasympathetic fibres are usually non-myelinated and shorter than the sympathetic, since the ganglia in which they synapse are in or near the viscera they supply. Baumann and Gajisin (1975) have emphasized the occurrence of small subsidiary ganglia near those mentioned above, confirming reports by others; they also described minute ganglia at many other sites in fetal material, for example along the middle meningeal artery and in some petrosal nerves.

1. Oculomotor preganglionic parasympathetic fibres commence in the midbrain at the accessory oculomotor (Edinger-Westphal) nuclei (p. 1227) and travel in the nerve in its branch to the inferior oblique to reach the ciliary ganglion. There they synapse, the post-ganglionic fibres leaving in the short ciliary nerves which pierce the sclera to run forwards in the perchoroidal space to the ciliary muscle (p. 1328) and the sphincter pupillae (p. 1331). These postganglionic axons are thinly myelinated.

2. The facial nerve contains preganglionic parasympathetic axons of neurons with their somata in the superior salivatory nucleus (p. 1243), emerging from the medulla oblongata in the nervus intermedius. These fibres leave the main facial trunk above the stylomastoid foramen in the chorda tympani, which traverses the tympanic cavity to reach the lingual nerve (p 1246). Thus they are conveyed to the submandibular ganglion, in which arise postganglionic secretomotor fibres for the submandibular salivary gland. Some preganglionic fibres may synapse around cells in the hilum of the gland (pp 1693, 1698). Postganglionic secretomotor fibres for the sublingual gland continue in the lingual nerve from the submandibular ganglion (pp 1247, 1693). Stimulation of chorda tympani dilates the arterioles in both glands in addition to having a direct secretomotor effect. The facial nerve is also usually said to contain efferent parasympathetic lacrimal secretomotor axons, which travel in its greater petrosal ramus and in the nerve of the pterygoid canal, relaying in the pterygopalatine ganglion. Postganglionic axons are said to travel by the zygomatic nerve to the lacrimal gland (p. 1235) and by ganglionic branches to the nasal and palatal glands. Evidence refuting the zygomatic route has been reported by Ruskell (1971), who favors direct lacrimal rami from a retro-orbital plexus of parasympathetic branches from the pterygopalatine ganglion. Clinical evidence suggests that some facial parasympathetic fibres reach the paratid gland (Diamant & Wiberg 1965 and p. 1243).

3. The glossopharyngeal nerve contains preganglionic parasympathetic secretomotor fibres for the parotid gland. These start in the inferior salivatory nucleaus (p. 1250) and travel in the glossopharyngeal nerve and its tympanic branch. They traverse the tympanic plexus and lesser petrosal nerve to reach the otic ganglion where they relay, the postganglionic fibres passing by communicating branches to the auriculotemporal nerve, which conveys them to the parotid gland. Stimulation of the lesser petrosal nerve produces vasodilator and secretomotor effects.

4. The vagus nerve contains preganglionic parasympathetic fibres whoich arise in its dorsal nucleus (p. 1251) and travel in the nerve and its pulmonary, cardiac, oesophageal, gastric, intestinal, and other branches. Some cardiac parasympathetic fibres may originate from neurons in or near the nucleus ambiguus (p. 1021). The proportion of efferent parasympathetic fibres in the vagus varies at different levels but is small relative to its sensory and sensory-motor content. Efferent fibres relay in minute ganglia in the visceral walls. The disproportion in the numbers of preganglionic to postganglionic fibres is greater in the vagus than in other cranial nerves; this cannot as yet be explained. Cardiac branches slow the cardiac cycle, joining the cardiac plexuses (p. 1306) and relaying in ganglia distributed freely over both atria in the subepicardial tissue (10.59), terminal fibres being distributed to the atria and the atrioventricular (AV) bundle and concentrated around the SA and (to a lesser extent) the AV nodes. It has been claimed in the past that only through the latter can the vagi influence ventricular muscle (Cullis & Tribe 1913), although there is a sparse postganglionic parasympathetic innervation of the ventricles (Higgins et al 1973). The smaller branches of the coronary arteries are innervated mainly via the vagus; larger arteries, with a dual innervation, are chiefly supplied by sympathetic fibres (Wollard 1926; Lundberg et al 1983; Owman 1988). Pulmonary branches are motor to the circular non-striated muscle fibres of the bronchi and bronchioles and are therefore bronchoconstrictor; synaptic relays occur in the ganglia of the pulmonary plexuses. Gastric branches are secretomotor and motor to the non-striated muscle of the stomach, with the exception of the pyloric sphincter, which they inhibit. Intestinal branches have a corresponding action in the small intestine, caecum, vermiform appendix, ascending colon, right colic flexure, and most of the transverse colon; they are secretomotor to the gonads, motor to the intestinal muscular coats but inhibitory to the ileocaecal sphincter. The synaptic relays are situated in the myenteric (Auerbach's) and the submucosal (Meissner's) plexuses (p. 1747).

5. The anterior rami of the second, third, and often fourth sacral spinal nerves issue pelvic splanchnic nerves (8.381) to the pelvic viscera. These nerves unite with branches of the sympathetic pelvic plexuses. Minute ganglia occur at the points of union and in the visceral walls. In these ganglia the sacral preganglionic parasympathetic fibres relay synaptically.

The pelvic splanchnic nerves are motor to the muscle of the rectum and bladder wall but inhibitory to the vesical sphincter, supply vasodilator fibres to the penile and clitoridic erectile tissue and are probably vasodilator to the testes and ovaries and vasodilator (and possibly inhibitory ) to the uterine tubes and uterus (de Groat 1992). Filaments from the pelvic splanchnic nerves ascend in the hypogastric plexus to supply the sigmoid and descending colon, the left colic flexure and terminal transverse colon with visceromotor fibres (Telford & Stopford 1934; Mitchell 1935; Christenson et al 1984).

Next, the sympathetics in some involved detail.

[Diane]

SYMPATHETIC NERVOUS SYSTEM: EFFERENT PATHWAYS

P. 1298 Gray's:

SYMPATHETIC NERVOUS SYSTEM
The sympathetic system includes the two ganglionated trunks and their branches. plexuses and subsidiary ganglia. It has a much wider distribution than the parasympathetic, for it innervates
- all sweat glands
- the arrectores pilorum
- the muscular walls of many blood vessels
- the heart
- lungs and respiratory tree
- the abdomino-pelvic viscera
- oesophagus
- muscles of the iris in the eye
- non-striated muscle of the urogenital tract, eyelids and elsewhere.

There are differences in the pattern of sympathetic innervation of different effector tissues; for example, visceral smooth muscles such as the vas deferens and iris receive a dense varicose nerve plexus throughout with close, 20 nm neuromuscular separations, while most blood vessels receive an innervation which is confined to the adventitial-medial border with neuromuscular separations often greater than 80 nm.

EFFERENT PATHWAYS
The preganglionic fibres are axons of somata in the lateral grey column of all the thoracic and the upper two or three lumbar spinal segments, where they form intermediomedial and intermediolateral neuronal groups (p. 980). The axons are myelinated, with diameters of 1.5 - 4 um, and emerge from the spinal cord through the ventral spinal roots, passing into the spinal nerves at the start of their ventral rami, which they soon leave in white rami communicantes, to join either the corresponding ganglia of the sympathetic trunks or their interganglionic segments. This outflow is confined to the thoracolumbar region, the white rami communicantes being restricted to these 14 pairs of spinal nerves, although a limited outflow in other spinal nerves has been suggested. Neurons like those in the lateral grey column exist at other levels of the cord above and below the thoracolumbar outflow (Mitchell 1953) and small numbers of their fibres issue in other ventral roots. Dorsal spinal roots may also contain vasodilator fibres. Reaching the sympathetic trunk, preganglionic fibres may behave in several ways:
1. They may synapse with neurons in the nearest ganglion.
2. They may traverse this, ascending or descending in the sympathetic chain to end in another ganglion; note however that preganglionic fibres do not divide into ascending and descending branches. A single preganglionic fibre may, through collateral and terminal branches, synapse with neurons in several ganglia or terminate in only one ganglion.
3. They may traverse the nearest ganglion, ascend or descend and, without synapsing, emerge in one of the medially-directed branches of the sympathetic trunk to end at synapses in the ganglia of autonomic plexuses (mainly situated in the midline, for example around the coeliac and mesenteric arteries, p. 1307). Occasionally preganglionic fibres relay in ganglia situated proximal to the sympathetic trunks; these 'intermediate ganglia' are most numerous on grey rami communicantes (see below) at cervical and lower lumbar levels; they may be of microscopic size and sometimes occur in ventral roots or trunks. More than one preganglionic fibre may synapse with a single postganglionic neuron (see below).

The nervi terminales (p. 1225) may be rostral extensions of the sympathetic system, containing efferent postganglionic fibres distributed to the blood vessels and glands of the nasal cavity, although this view has been challenged (Bojsen-Moller 1975).

The sympathetic ganglia include collections of cells on the sympathetic trunks, in the autonomic plexuses and the 'intermediate' ganglia; some ganglionic cells are dispersed in the plexuses. Originally ganglia on the trunks correspond numerically to the ganglia on the dorsal spinal roots (p. 1261); but adjoining ganglia may fuse and there are rarely more than 22 or 23 and sometimes fewer. Subsidiary ganglia in the major autonomic plexuses (e.g. coeliac, superior mesenteric ganglia, etc.) are derivatives of the ganglia of the trunks. The functional properties of sympathetic ganglia have been investigated extensively over many decades, their peripheral location providing a valuable means of studying interneuronal communication, as well as other aspects of neurobiology (for reviews of the earlier literature see p 1292; more recent accounts are given by Gabella (1976), Eranko (1978), Elfvin (1983) and Szurszewski and King (1989).

Next; Structure of the sympathetic ganglia.
Tip: Imagine all this horizontal, as if in a quadruped, spine/spinal cord at the top, aorta running along it beneath/next story below covered in regulatory nerve net, chain ganglia along it, then some more cross wiring/big ganglia suspended between aorta and the belly/gut tube/endodermic system below that, everything surrounded by a spherical body wall balloon that has 4 parallel legs protruding downward and a head sticking out from it. It's easier to see the logic in the hookups that way. At least it is for me. Oh, and the balloon has a sensitive second balloon surrounding it which is slidey over it.

[Diane]

Structure of sympathetic ganglia

P. 1298 Gray's:

Structure of sympathetic ganglia
The classic studies by Langley and his successors led to the view that the autonomic ganglia are relay stations, a concept largely corroborated by anatomical observation, although it was soon recognized that a minor fraction of the fibres traversed one or more ganglia without synapse, some being efferent fibres on route to another ganglion and others afferents from the viscera and glands. This concept remains substantially true but has been modified and extended by electron microscopy, neurohistochemistry and electrophysiology, for example a considerable variation in the ratio between pre-and postganglionic fibres has been found (consult Skok 1973). The superior cervical sympathetic ganglion, the most extensively studied, has ratios varying from 1:28 to 1:176 in different mammalian species (Billingsley & Ranson 1918; Samuel 1953; Ebbesson 1968). It has long been accepted that preganglionic axons may synapse with many postganglionic neurons for the wide dissemination and perhaps amplification of sympathetic activity, a characteristic not shared to the same degree by parasympathetic ganglia. Dissemination may be achieved by:

- multiple synapses of preganglionic nerve fibres
- the mediation of interneurons
- the diffusion within the ganglion of transmitter substances locally produced (paracrine effect) or by a local response to a substance produced elsewhere (endocrine effect).

There is evidence that all of these mechanisms are involved. The connective tissue capsule of each ganglion, continuous with the epineurium of its connecting rami, also extends as septa into the ganglion, the surrounding groups of neurons and their fibres. More delicate extensions of this stroma spread amongst the cells, each of which is surrounded by a collagenous intercellular matrix containing a few fibroblasts and many small vessels including capillaries. Satellite cells (amphicytes) encapsulate the somata of ganglionic neurons and their processes. Externally this thin sheath of satillite cells has a continuous basal lamina and the two elements screen neurons from contact with the ganglionic extracellular matrix. Neurons thus have direct access only to the internal faces of satellite cells, the two being separated only by a narrow perineurial space of 15-20 nm which is, however, linked to the extracapsular spaces by narrow channels between the satellite cells, providing possible routes for the movement of nerotransmitter and hormonal substances between the somata of neurons and the vascular compartment.

Attempts to classify the neurons of the sympathetic (and parasympathic) ganglia, often on inadequate criteria, have entailed disagreements and confusion. Most are multipolar, with somata ranging from 25-50 um in mankind; a smaller type of about 15-20 um, less angular in shape and present in much smaller numbers, is often clustered in groups (De Castro & Herreros 1945) and probably corresponds to 'small intensely flourescent' (SIF) cells (see below). Multipolar neurons display much more dendritic variation; according to McLachlan (1974) they have (in guinea pigs) a mean of 13 dendrites per cell. The complexity of these dendrites, especially those ramifying in the capsular perikaryal space, is greater in human ganglion cells. Dendritic glomeruli have been observed in many ganglia. In general ultrastructure these glomeruli resemble others (p. 934); clusters of small, granular vesicles, adrenergic in type, are dispersed superficially in the perikaryon and also in the dendrites, probably representing the storage of catacholomines. Ganglionic neurons receive many axodendritic synapses from preganglionic nerve fibres, the axosomatic synapses being less numerous. Each preganglionic fibre forms several synapses with several separate dendrites, providing a mechanism for the dissemination and/or amplification of neural signals. Post ganglionic fibres (see below) commonly arise from the initial stem of a large dendrite and produce few or no collateral neurites.

So the signal gets amped up and modulated right in the ganglia, by the wiring pattern itself being recursive and by how molecules of substances from elsewhere can come in to affect the neurons in strategic places. Next, interneurons.