Mol Pain
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Small neurons of the dorsal root ganglion (DRG) express five of the nine known voltage-gated sodium channels. Each channel has unique biophysical characteristics which determine how it contributes to the generation of action potentials (AP). To better understand how AP amplitude is maintained in nociceptive DRG neurons and their centrally projecting axons, which are subjected to depolarization within the dorsal horn, we investigated the dependence of AP amplitude on membrane potential, and how that dependence is altered by the presence or absence of sodium channel Nav1.8. ⋯ We conclude that the presence of Nav1.8 allows AP amplitude to be maintained in DRG neurons and their centrally projecting axons even when depolarized within the dorsal horn.
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Accumulating evidence over last several years indicates an important role of microglial cells in the pathogenesis of neuropathic pain. Signal transduction in microglia under chronic pain states has begun to be revealed. ⋯ We will also discuss the downstream mechanisms by which p38 produces inflammatory mediators. Taken together, current data suggest that p38 plays a critical role in microglial signaling under neuropathic pain conditions and represents a valuable therapeutic target for neuropathic pain management.
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In general, opioids that induce the recycling of mu-opioid receptors (MORs) promote little desensitization, although morphine is one exception to this rule. While morphine fails to provoke significant internalization of MORs in cultured cells, it does stimulate profound desensitization. In contrast, morphine does promote some internalization of MORs in neurons although this does not prevent this opioid from inducing strong antinociceptive tolerance. ⋯ In the nervous system, morphine induces a strong desensitization before promoting the phosphorylation and recycling of MORs. The long-term sequestering of morphine-activated Galpha subunits by certain RGS proteins reduces the responses to this opioid in neurons. This phenomenon probably increases free Gbetagamma dimers in the receptor environment and leads to GRK phosphorylation and internalization of the MORs. Although, the internalization of the MORs permits the transfer of opioid-activated Galpha subunits to the RGSZ2 proteins, it interferes with the stabilization of this regulatory process and recycled MORs recover the control on these Galpha subunits and opioid tolerance develops slowly.
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An understanding of how the brain changes in chronic pain or responds to pharmacological or other therapeutic interventions has been significantly changed as a result of developments in neuroimaging of the CNS. These developments have occurred in 3 domains : (1) Anatomical Imaging which has demonstrated changes in brain volume in chronic pain; (2) Functional Imaging (fMRI) that has demonstrated an altered state in the brain in chronic pain conditions including back pain, neuropathic pain, and complex regional pain syndromes. In addition the response of the brain to drugs has provided new insights into how these may modify normal and abnormal circuits (phMRI or pharmacological MRI); (3) Chemical Imaging (Magnetic Resonance Spectroscopy or MRS) has helped our understanding of measures of chemical changes in chronic pain. Taken together these three domains have already changed the way in which we think of pain - it should now be considered an altered brain state in which there may be altered functional connections or systems and a state that has components of degenerative aspects of the CNS.
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Endothelin-1 (ET-1) both stimulates nociceptors and sensitizes them to noxious stimuli, an effect probably mediated by the ETA receptor (ETAR) expressed in sensory neurons. The cellular mechanisms of this ET-1-mediated effect are only poorly understood. TRPV1, the heat-, pH- and capsaicin-sensitive cation channel already known to be modulated by a number of cellular mediators released in response to noxious stimuli and during inflammation, is a potential target for the action of ET-1. ⋯ We conclude that ET-1 potentiates TRPV1 by a PKC-dependent mechanism and that this could play a major role in the algogenic and hyperalgesic effects of ET-1 described in previous studies.