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However, the main serotonin receptor subtype that modulates the MSR is the 5-HT1D receptor that is expressed almost exclusively on nociceptive C-fibres, suggesting an unexpected gating of proprioceptive transmission by regulation of nociceptive pathways. We demonstrate here that activation of C-fibres (electrically or pharmacologically by TRPM8 agonists) increases action potential propagation in proprioceptive Ia afferents by producing a very long-lasting tonic depolarization in Ia afferents (tonic primary afferent depolarization, tonic PAD). This tonic PAD is produced indirectly by C-fibres augmenting axoaxonic GABAergic input onto Ia afferents (bicuculline sensitive), which activates nodal GABAA receptors that aid sodium spike initiation. In contrast, activation of 5-HT1D receptors with the anti-migraine drug zolmitriptan inhibits C-fibre activity, which in turn reduces the GABAA receptor-mediated tonic PAD on Ia afferents, and reduces spike propagation to motoneurons. Overall, these findings demonstrate a mechanism by which brainstem derived serotonin not only inhibits ongoing nociceptive C-fibres activity, but also indirectly inhibits GABAergic neurons and sensory transmission in large proprioceptive sensory afferents, leading to reduced motoneuron activity. Furthermore, these findings suggest that spontaneous nociceptive C-fibres activity may provide a general increase in proprioception, opposite to the classical gating of nociceptive pathways by low threshold afferents, and impacting the clinical use of zolmitriptan.<\/jats:p>","DOI":"10.64898\/2026.02.02.703408","type":"posted-content","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T11:00:18Z","timestamp":1770289218000},"source":"Crossref","is-referenced-by-count":2,"title":["GABAA receptor mediated facilitation of proprioceptive afferent transmission to motoneurons is facilitated by TRPM8 channels on C-fibres that are gated by serotonin"],"prefix":"10.64898","author":[{"given":"Sophie","family":"Black","sequence":"first","affiliation":[{"name":"Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqing","family":"Li","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada"},{"name":"Department of Cell Biology, Emory University, Atlanta, GA, 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishnapriya","family":"Hari","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihao","family":"Lin","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole De","family":"Silvia","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Temitayo","family":"Ayantayo","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilee J.","family":"Stephens","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada"},{"name":"Department of Biomedical Engineering, Faculty of Medicine and Dentistry, T6G 2V2, University of Alberta, Edmonton, AB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith K.","family":"Fenrich","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada"},{"name":"Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, AB, T6G 2G4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana M.","family":"Lucas-Osma","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada"},{"name":"Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, AB, T6G 2G4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire F.","family":"Meehan","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Copenhagen"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica A.","family":"Gorassini","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada"},{"name":"Department of Biomedical Engineering, Faculty of Medicine and Dentistry, T6G 2V2, University of Alberta, Edmonton, AB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada"},{"name":"Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, AB, T6G 2G4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026021607100673000_2026.02.02.703408v3.1","doi-asserted-by":"crossref","unstructured":"Mentis GZ , Alvarez FJ , Shneider NA , Siembab VC , and O\u2019Donovan MJ . 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