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Leaky Gate Model: Intensity-Dependent Coding of Pain and Itch in the Spinal Cord

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  • Ref Leaky Gate Model: Intensity-Dependent Coding of Pain and Itch in the Spinal Cord

    http://www.cell.com/neuron/fulltext/...273(17)30036-3

    Highlights
    •Grp+ neurons receive monosynaptic input from both pain and itch primary neurons
    •Intensity-dependent coding of pain by Grp+ neurons
    •Grp+ neurons form “leaky gate” to negatively regulate pain transmission
    •Loss of Grp+ neurons decreases itch and increases pain
    Summary
    Coding of itch versus pain has been heatedly debated for decades. However, the current coding theories (labeled line, intensity, and selectivity theory) cannot accommodate all experimental observations. Here we identified a subset of spinal interneurons, labeled by gastrin-releasing peptide (Grp), that receive direct synaptic input from both pain and itch primary sensory neurons. When activated, these Grp+ neurons generated rarely seen, simultaneous robust pain and itch responses that were intensity dependent. Accordingly, we propose a “leaky gate” model in which Grp+ neurons transmit both itch and weak pain signals; however, upon strong painful stimuli, the recruitment of endogenous opioids works to close this gate, reducing overwhelming pain generated by parallel pathways. Consistent with our model, loss of these Grp+ neurons increased pain responses while itch was decreased. Our new model serves as an example of non-monotonic coding in the spinal cord and better explains observations in human psychophysical studies.
    Jo Bowyer
    Chartered Physiotherapist Registered Osteopath.
    "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

  • #2


    via @dibbygibby
    Jo Bowyer
    Chartered Physiotherapist Registered Osteopath.
    "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

    Comment


    • #3
      Do these authors propose a model where pain is actualy encoded peripherally ?
      Marcel

      "Evolution is a tinkerer not an engineer" F.Jacob
      "Without imperfection neither you nor I would exist" Stephen Hawking

      Comment


      • #4
        Debates about pain and itch coding have been ongoing for decades. One major theory, the intensity theory, claims that polymodal sensory neurons respond to both painful and itchy stimuli.
        Another major theory is the labeled-line theory, which argues that different senses are coded by mutually exclusive populations (Norrsell et al., 1999, Schmelz et al., 1997). However, the fact that itch-responsive neurons are also activated by painful stimuli argues against the labeled-line theory.
        The selectivity theory suggests that itchy stimuli specifically activate itch-selective neurons to generate itch sensation, while painful stimuli activate both itch-selective neurons and a larger nociceptive population whose activation inhibits itch to produce only pain sensation.
        Recent studies largely support this modified labeled-line theory. In DRG, Han et al. (2013)) confirmed the existence of “itch-selective” neurons by showing that the activation of the MrgprA3+ primary sensory neurons generated itch but not pain responses, while its ablation impaired itch and spared pain (Han et al., 2013).
        We identified a subset of second-order neurons, positive for Grp, that receive direct synaptic inputs from both pain and itch primary sensory neurons. Surprisingly, the activation of the Grp+ neurons generated both pain and itch responses, with the pain coding being intensity dependent.
        Grp has previously been implicated in itch transmission. Grp was reported to express in DRG, but not in spinal cord, and had been proposed to provide input to GRPR+ neurons (Sun and Chen, 2007). However, recent studies suggest that Grp instead expresses in spinal cord dorsal horn, not the DRG (Fleming et al., 2012, Solorzano et al., 2015).
        my italics

        Coding of Both Pain and Itch by Grp+ Neurons
        Although the itch neurons in DRG are responsive to both painful and itchy stimuli, activation of these neurons generates itch and not pain responses (Han et al., 2013). Similarly, Grp+ neurons appear to receive direct synaptic input from both pain and itch primary neurons.


        What I take from this, is the coding for both happens at cord level and above.



        Local GABAergic signaling within sensory ganglia controls peripheral nociceptive transmission
        https://www.jci.org/articles/view/86812

        Abstract
        Quote:
        The integration of somatosensory information is generally assumed to be a function of the central nervous system (CNS). Here we describe fully functional GABAergic communication within rodent peripheral sensory ganglia and show that it can modulate transmission of pain-related signals from the peripheral sensory nerves to the CNS. We found that sensory neurons express major proteins necessary for GABA synthesis and release and that sensory neurons released GABA in response to depolarization. In vivo focal infusion of GABA or GABA reuptake inhibitor to sensory ganglia dramatically reduced acute peripherally induced nociception and alleviated neuropathic and inflammatory pain. In addition, focal application of GABA receptor antagonists to sensory ganglia triggered or exacerbated peripherally induced nociception. We also demonstrated that chemogenetic or optogenetic depolarization of GABAergic dorsal root ganglion neurons in vivo reduced acute and chronic peripherally induced nociception. Mechanistically, GABA depolarized the majority of sensory neuron somata, yet produced a net inhibitory effect on the nociceptive transmission due to the filtering effect at nociceptive fiber T-junctions. Our findings indicate that peripheral somatosensory ganglia represent a hitherto underappreciated site of somatosensory signal integration and offer a potential target for therapeutic intervention.
        So far as I know humans produce traffic within the PNS. Octopuses, octopi? probably can code within their PNS, if what they have is a PNS. I would argue that their brains extend throughout their bodies.

        Update 08/04/2017





        The Cellular and Synaptic Architecture of the Mechanosensory Dorsal Horn

        http://www.cell.com/cell/fulltext/S0092-8674(16)31684-1

        Highlights
        •Convergent LTMR and cortical inputs define the mechanosensory dorsal horn
        •A dorsal horn molecular-genetic toolbox defines 11 interneuron subtypes
        •Dorsal horn interneurons receive specific patterns of cortical and LTMR inputs
        •Dorsal horn interneurons modulate output pathways and tactile perception

        Summary
        The deep dorsal horn is a poorly characterized spinal cord region implicated in processing low-threshold mechanoreceptor (LTMR) information. We report an array of mouse genetic tools for defining neuronal components and functions of the dorsal horn LTMR-recipient zone (LTMR-RZ), a role for LTMR-RZ processing in tactile perception, and the basic logic of LTMR-RZ organization. We found an unexpectedly high degree of neuronal diversity in the LTMR-RZ: seven excitatory and four inhibitory subtypes of interneurons exhibiting unique morphological, physiological, and synaptic properties. Remarkably, LTMRs form synapses on between four and 11 LTMR-RZ interneuron subtypes, while each LTMR-RZ interneuron subtype samples inputs from at least one to three LTMR classes, as well as spinal cord interneurons and corticospinal neurons. Thus, the LTMR-RZ is a somatosensory processing region endowed with a neuronal complexity that rivals the retina and functions to pattern the activity of ascending touch pathways that underlie tactile perception.

        Wired for touch: the neurons and circuits of the somatosensory system

        http://www.bodyinmind.org/neurons-ci...ody+in+Mind%29

        I have posted this here for context re processing.
        Last edited by Jo Bowyer; 08-06-2017, 12:15 AM.
        Jo Bowyer
        Chartered Physiotherapist Registered Osteopath.
        "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

        Comment


        • #5
          Placebo Analgesia: A Predictive Coding Perspective

          http://www.sciencedirect.com/science...96627314001925

          The Site of Modulation

          Pain is a psychologically constructed experience that includes extensive processing at the cortical level (Apkarian et al., 2005 and Tracey and Mantyh, 2007). A mechanism subserving placebo hypoalgesia could therefore theoretically be implemented at the cortical or subcortical level. In agreement with this idea, initial studies on placebo hypoalgesia firmly established the involvement of the rACC and prefrontal cortex (PFC) with projections to the PAG in placebo hypoalgesia (Bingel et al., 2006, Petrovic et al., 2002 and Wager et al., 2004). These early studies supported the view that “a major portion of the placebo effect may be mediated centrally by changes in specific pain regions” (Wager et al., 2004). However, several years later, a series of placebo hypoalgesia experiments demonstrated effects in relation to placebo hypoalgesia in the medulla (Eippert et al., 2009b; note that Petrovic and colleagues, 2002 already observed placebo-related signal changes in an area close to the RVM) and even at the spinal cord level (Eippert et al., 2009a and Matre et al., 2006). These observations speak against a model in which placebo hypoalgesia is an exclusively supraspinal phenomenon, but rather suggest that placebo hypoalgesia is implemented through a hierarchical recurrent system including cortical (rACC and AI), subcortical (AMY, HT, and THA), midbrain (PAG), medulla (RVM), and spinal sites.
          my bold
          Last edited by Jo Bowyer; 25-02-2017, 06:35 PM.
          Jo Bowyer
          Chartered Physiotherapist Registered Osteopath.
          "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

          Comment

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