Thermosensation is an essential sensory function that is subserved by a variety of transducer molecules, including those from the Transient Receptor Potential (TRP) ion channel superfamily. One of its members, TRPM8 (CMR1), a ligand-gated, nonselective cation channel, is activated by both cold and chemical stimuli in vitro. However, its roles in cold thermosensation and pain in vivo have not been fully elucidated. Here, we show that sensory neurons derived from TRPM8 null mice lack detectable levels of TRPM8 mRNA and protein and that the number of these neurons responding to cold (18 degrees C) and menthol (100 microM) is greatly decreased. Furthermore, compared with WT mice, TRPM8 null mice display deficiencies in certain behaviors, including icilin-induced jumping and cold sensation, as well as a significant reduction in injury-induced responsiveness to acetone cooling. These results suggest that TRPM8 may play an important role in certain types of cold-induced pain in humans.
It has been suggested that neuroimmunologic mechanisms may be involved in the development and maintenance of neuropathic pain. To further address this concept, the immunoreactive spinal expression of the pro-inflammatory cytokine, interleukin-6 (IL-6), was determined in the mononeuropathy model in the rat, sciatic cryoneurolysis (SCN). This well-established animal model expresses behaviors suggestive of neuropathic pain in humans. Immunohistochemical localization in the spinal cord was determined at 3, 7, 14, 21, 35, and 120 days after SCN (n = 6 per time point). Immunoreactive IL-6 increased incrementally in the substantia gelatinosa and motoneurons over time following SCN as compared with normal rats. In an additional study, recombinant human IL-6 was administered intrathecally to normal and previously SCN-lesioned rats. Intrathecal IL-6 produced touch-evoked allodynia (increased sensitivity to a nonnoxious stimulus) in normal rats and thermal hyperalgesia (increased sensitivity to a noxious stimulus) in previously lesioned SCN rats. These results provide evidence that IL-6 may be involved in the cascade of events leading to the development and maintenance of behaviors suggestive of neuropathic pain following peripheral nerve injury.
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