Suppression of neuropathic pain hypersensitivity by TRPM8 is mediated by mGluR group II and III receptors acting differentially on distinct nociceptor inputs to spinal cord

Background: Chronic pain following nerve injury (neuropathic pain), is notoriously difficult to treat, with current analgesics showing limited efficacy and adverse or dangerous side effects. One new candidate analgesic target is the TRPM8 ion channel, identified as the peripheral detector for innocuous cool sensation and reported to attenuate spinal cord pain processing by processes involving inhibitory metabotropic glutamate (mGlu) receptors. Methods: reflex pain behaviours. Results: antagonists impacted TRPM8 attenuation of nerve injury-induced synaptic hypersensitivity at spinal and also supraspinal regions of the CNS associated with pain processing. Conclusion: , respectively. This provides robust evidence to support the fundamental concept of distinct parallel processing and differential modulation of these classes of inputs. This work extends our understanding of the basis for TRPM8 analgesia, identifies distinct modality-specific processes and points to the possibility of refined therapeutic interventions using mGluR modulators as adjunct promoters of particular elements of analgesia.