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Pain and Inflammation

Cardinal signs of inflammation. RuborCalorTurgorDolor. Or in plain language:Heat and redness ? due to increased local blood flowSwelling ? due to increased microvascular permeabilityPain and tendernessNote also that inflammation is accompanied by infiltration of inflamed tissues by cells of t

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Pain and Inflammation

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    1. Pain and Inflammation Lecture 4 Fundamentals of Pain, PHOL G008 Bruce Lynn Director, MSc School of human Health and Performance

    2. Cardinal signs of inflammation Rubor Calor Turgor Dolor

    3. How are pain and tenderness produced?

    4. Sensitization Lowered threshold Increased supra-threshold firing Spontaneous firing

    5. Sub classes of nociceptor in skin

    6. Large heat stimulus causes sensitization increased suprathreshold firing background “spontaneous” activity reduced threshold Heat sensitization C polymodal nociceptor innervating rabbit skin. From: Lynn B, 1979, j. physiol. 287, 493-507 (HT_SENS.PPT)Heat sensitization C polymodal nociceptor innervating rabbit skin. From: Lynn B, 1979, j. physiol. 287, 493-507 (HT_SENS.PPT)

    8. Graphical representation of nociceptor sensitization

    9. Graphical representation of nociceptor sensitization Spontaneous firing

    10. All classes of nociceptor sensitize Polymodal nociceptors increase heat and/or pressure responses Sleeping (silent)nociceptors awaken and respond like polymodals; Heat nociceptors become sensitized and begin firing to noxious pressure, i.e. they get more like polymodal nociceptors; Mechanical nociceptors sometimes become more sensitive to pressure and may become heat sensitive, but of the different types of nociceptor this group are least affected by inflammation.

    11. Effect of cooling skin Spontaneously firing nociceptor is quietened by applying ice to the skin

    12. Mediators of sensitization Many different mediators can cause sensitization including: Histamine Bradykinin 5-HT Also other agents not traditionally considered mediators but released during inflammation, e.g. H+ ions Nerve growth factor (NGF) In model systems of "real" inflammation, blockers of single mediators have little action on sensitization, so probably multiple mediators are involved.

    13. How do mediators sensitize? Bradykinin at least partly via protein kinase C. But recently proposed to also act via release of the VR1 receptor from a PtdIns(4,5)P2-mediated inhibition Prostaglandins act via cAMP, protein kinase A, and possibly by activating tetrodotoxin resistant sodium channels that are upregulated in inflammation. A number of mediators, including prostaglandins and 5-HT, can activate kinases that phosphorylate the TRPV1 channel and increase its probability of opening.

    21. Hyperalgesia. The behavioural and sensory consequence of sensitization Pain, but also hyperalgesia, characterises areas of inflammation. Hyperalgesia = increased pain to stimuli that are normally painful plus usually some fall in pain threshold. When the threshold falls a lot, so that light stimuli are painful, this is usually called ALLODYNIA. Other definitions exist, but the above encapsulates common usage.

    22. Graphical representation of hyperalgesia Spontaneous pain

    23. Secondary hyperalgesia Hyperalgesia is not restricted to the zone of direct inflammation, but also spreads to surrounding uninflamed areas, called secondary hyperalgesia. Nociceptors are not sensitized in this area. Most likely mechanism is central convergence at dorsal horn and higher levels, plus increased central excitability (wind-up; central sensitization).

    29. Neurogenic inflammation, NGI Due to release of vasoactive neuropeptides from nociceptive nerve endings (e.g. calcitonin gene-related peptide [CGRP] and substance P). Many nociceptors (mostly heat noci or other mech insensitive nocis) thus have efferent as well as afferent actions. Pre-treatment with capsaicin poisons these afferents, so after this there is no NGI. Capsaicin pre-treatment reduces inflammation in several "models", e.g. some experimental arthritis models and sunburn (UV-induced inflammation), suggesting that neurogenic inflammation is a factor in these situations. In theory we could get a "vicious circle" where neuropeptide release activates release of irritant mediators that excite C terminals causing more neuropeptide release and so on for ever. Evidence for this type of self-sustaining reaction has not been found – yet!

    30. Summary · Inflammatory mediators sensitize nociceptors, leading to spontaneous firing and increased responses to stimuli. ·  These changes are presumed to be the main causes of pain and hyperalgesia. ·  Pain and hyperalgesia are amplified and caused to spread by central changes, e.g. wind-up in the dorsal horn. ·  Many C-nociceptors can release pro-inflammatory peptides that play a significant role in inflammation, a unique efferent role for an "afferent" neurone.

    31. Reading – Pain and Inflammation Review Hunt, S.P. & Mantyh, P.W. (2001) The molecular dynamics of pain control. Nature Reviews Neuroscience, 2, 83-91 Peripheral mechanisms Review. McMahon, S. B., Bennett, D/L.H. & Bevan, S. (2005). Inflammatory mediators and modulators of pain. In Textbook of Pain, eds McMahon, S.B. & Koltzenburg, M. Chapt 3. Gold, M. S., Reichling, D. B., Shuster, M. J., & Levine, J. D. Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors. Proc.Natl.Acad.Sci.U.S.A. 93[3], 1108-1112. 1996. Chuang, H. H., Prescott, E. D., et al (2001). Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411, 957-962. Ohta, T. et al (2006) Potentiation of transient receptor potential V1 functions by the activation of metabotropic 5-HT receptors in rat primary sensory neurons. J Physiol 576, 809-823. Central sensitization Review. Woolf, C. J & Salter, M. W. (2005). Plasticity and pain: role of the dorsal horn. In Textbook of Pain, eds McMahon, S.B. & Koltzenburg, M. Chapt 5.  Neurogenic inflammation Lynn, B. (1996) Neurogenic inflammation caused by polymodal receptors. Prog Brain Research 113, 361-8.

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