{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T06:12:57Z","timestamp":1776147177443,"version":"3.50.1"},"reference-count":161,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Highly selective Group II\/III mGluR antagonists and allosteric modulators were used in a nerve injury model to identify the specific receptor subtypes mediating TRPM8-mediated attenuation of nociceptive (pain) processing through peptidergic and non-peptidergic afferent inputs (associated with thermal and mechanical nociception respectively). Integrated experimental approaches involved immunofluorescence histochemistry, functional Ca\n                      <jats:sup>2+<\/jats:sup>\n                      fluorescence responses of\n                      <jats:italic>ex vivo<\/jats:italic>\n                      synaptoneurosomes and\n                      <jats:italic>in vivo<\/jats:italic>\n                      reflex pain behaviours.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Differential expression of TRPV1 and MrgprD was demonstrated in peptidergic and non-peptidergic afferents and their selective activation by capsaicin and \u03b2-alanine characterised to interrogate transmission at the first central synapses from these afferents in dorsal spinal cord synaptoneurosomes. TRPM8-evoked attenuation of nerve injury-induced increments in capsaicin responses was selectively modified by mGlu\n                      <jats:sub>8<\/jats:sub>\n                      -targetting agents whereas the equivalent effect on \u03b2-alanine responses was selectively modified by mGlu\n                      <jats:sub>2<\/jats:sub>\n                      -targetting agents. Other Group II\/III mGluR subtypes appeared not to be involved. Reflex pain behaviour assessments correspondingly pointed to mGlu\n                      <jats:sub>8<\/jats:sub>\n                      and mGlu\n                      <jats:sub>2<\/jats:sub>\n                      being selectively involved in TRPM8 attenuation of thermal and mechanical hypersensitivity respectively. Spinal administration of mGlu\n                      <jats:sub>2<\/jats:sub>\n                      and mGlu\n                      <jats:sub>8<\/jats:sub>\n                      antagonists impacted TRPM8 attenuation of nerve injury-induced synaptic hypersensitivity at spinal and also supraspinal regions of the CNS associated with pain processing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our findings clarify the roles of specific Group II\/III mGluRs in the antinociceptive effects of TRPM8 activation against nerve injury-induced hypersensitivity. The mGluRs involved in impacting peptidergic (thermal-associated) nociceptive inputs and non-peptidergic (mechanical-associated) nociceptive inputs appear quite distinct - mGlu\n                      <jats:sub>8<\/jats:sub>\n                      and mGlu\n                      <jats:sub>2<\/jats:sub>\n                      , 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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1806325","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T05:37:05Z","timestamp":1776145025000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["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"],"prefix":"10.3389","volume":"17","author":[{"given":"Rory","family":"Mitchell","sequence":"first","affiliation":[{"name":"Institute for Neuroscience and Cardiovascular Research, College of Medicine & Veterinary Medicine, University of Edinburgh","place":["Edinburgh, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liting","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute for Neuroscience and Cardiovascular Research, College of Medicine & Veterinary Medicine, University of Edinburgh","place":["Edinburgh, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Czapranska","sequence":"additional","affiliation":[{"name":"Institute for Neuroscience and Cardiovascular Research, College of Medicine & Veterinary Medicine, University of Edinburgh","place":["Edinburgh, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sue","family":"Fleetwood-Walker","sequence":"additional","affiliation":[{"name":"Institute for Neuroscience and Cardiovascular Research, College of Medicine & Veterinary Medicine, University of Edinburgh","place":["Edinburgh, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1021\/acsmedchemlett.7b00317","article-title":"Discovery of VU6005649, a CNS penetrant mGlu(7\/8) receptor PAM derived from a series of Pyrazolo[1,5-a]pyrimidines","volume":"8","author":"Abe","year":"2017","journal-title":"ACS Med. 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