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Nociceptor Processing

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Injury or inflammation leads to profound changes in nociceptor processing. Discuss how nociceptors could contribute to the development of pathological pain responses under (1) inflammatory and (2) neuropathic pain conditions. Provide specific mechanisms under each condition and be sure to reference primary literatures in your answer. Please note that your answer should address both inflammatory and neuropathic pain conditions.
Action on Transduction - A very logical mechanism to sensitize a nociceptor is to act on the stage of initial signal transduction, potentiating the process, and sensitizing the cell.
A major receptor on primary afferents necessary for signal transduction is TRPV1, which inflammatory factors can act on, changing the gating …show more content…
ATP, an inflammatory factor, binds P2X receptors and increases intracellular calcium which then works to potentiate TRPV1 receptors which will promote depolarization to threshold generating an action potential. Also, protons (so acidosis) often increase following inflammation and this low pH will then activate ASICs and TRPV1 (a truly polymodal receptor) acting as a positive allosteric modulator of the latter, promoting an open conformation which will lower noxious stimuli sensitivity, increasing sensitization. Inflammation induced sensitization does not have to work just through ionotropic receptors, but may also use GPCRs. Specific types of these receptors are activated via the inflammatory factors bradykinin and substance P, allowing the activation of the Gq protein and a triggering of a PKC …show more content…
This zone, as the name implies, is capable of generating action potentials when a certain threshold is reached. Inflammation may also alter the properties of sodium channels reducing the threshold to open. Inflammatory factors like arachidonic acid to COX then to prostaglandin, can activate Gs coupled receptors which activate a PKA pathway. PKA can act on voltage gated sodium channels, specifically the TTX resistant channels (expressed exclusively in nociceptors), which then phosphorylates this channels making them more excitable promoting action potential generation. PKA will also influence the expression of these ion channels promoting initiation. Also, on the neuropathic side of sensitization, it has been observed for many decades now that following nerve injury, that ectopic discharges emerge. Under normal conditions a nociceptor should not be firing without noxious stimulus, but this changes with nerve injury (Wall, 1974). Interestingly, not only the injured nerve can be affected in this manner by injury, but also its neighbors (Gold,2000). In the neuroma, following nerve injury, there is an upregulation of voltage gated sodium channels, which has been related to ectopic discharge. Therefore this upregulation must impact the initiation of firing (Devor,

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