Pain
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Menthol, the cooling natural product of peppermint, is widely used in medicinal preparations for the relief of acute and inflammatory pain in sports injuries, arthritis, and other painful conditions. Menthol induces the sensation of cooling by activating TRPM8, an ion channel in cold-sensitive peripheral sensory neurons. Recent studies identified additional targets of menthol, including the irritant receptor, TRPA1, voltage-gated ion channels and neurotransmitter receptors. ⋯ L-menthol- and WS-12-induced analgesia was blocked by naloxone, suggesting activation of endogenous opioid-dependent analgesic pathways. Our data show that TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain. In contrast to menthol, selective TRPM8 agonists may produce analgesia more effectively, with diminished side effects.
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Calcineurin (protein phosphatase 3) regulates synaptic plasticity in the brain. The development of neuropathic pain appears dependent on some of the same mechanisms that underlie brain synaptic plasticity. In this study, we examined whether calcineurin regulates chronic constriction injury (CCI)-elicited plasticity in the spinal dorsal horn. ⋯ CCI may elicit neuropathic pain at least in part as a result of the loss of calcineurin-mediated dephosphorylation in the dorsal horn. Addition of the phosphatase by intrathecal injection reverses the injury-elicited loss and provides prolonged pain relief. Clinical therapy with calcineurin may prove to be a novel, effective, and safe approach in the management of well-established neuropathic pain.
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Chronic neuropathic pain is often a severe and inadequately treated consequence of spinal cord injury (SCI). Recent findings suggest that SCI pain is promoted by spontaneous activity (SA) generated chronically in cell bodies of primary nociceptors in dorsal root ganglia (DRG). Many nociceptors express transient receptor potential V1 (TRPV1) channels, and in a preceding study most dissociated DRG neurons exhibiting SA were excited by the TRPV1 activator, capsaicin. ⋯ TRPV1 knockdown also decreased the incidence of SA in dissociated nociceptors after SCI. Prolonged application of very low concentrations of capsaicin produced nondesensitizing firing similar to SA, and this effect was enhanced by prior SCI. These results show that TRPV1 makes important contributions to pain-related hypersensitivity long after SCI, and suggest a role for TRPV1-dependent enhancement of nociceptor SA that offers a promising target for treating chronic pain after SCI.