Mol Pain
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Among different forms of persistent pain, neuropathic pain presents as a most difficult task for basic researchers and clinicians. Despite recent rapid development of neuroscience and modern techniques related to drug discovery, effective drugs based on clear basic mechanisms are still lacking. ⋯ I will present the problem of neuropathic pain as a rather difficult task for neuroscientists, and we may have to wait for a long time before we fully understand how brain encode, store, and retrieve painful information after the injury. I propose that neuropathic pain as a major brain disease, rather being a clinic problem due to peripheral injury.
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Animal and clinical studies have revealed that focal peripheral nerve axon demyelination is accompanied by nociceptive pain behavior. C-C and C-X-C chemokines and their receptors have been strongly implicated in demyelinating polyneuropathies and persistent pain syndromes. Herein, we studied the degree to which chronic nociceptive pain behavior is correlated with the neuronal expression of chemokines and their receptors following unilateral lysophosphatidylcholine (LPC)-induced focal demyelination of the sciatic nerve in rats. ⋯ These results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic 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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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.