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To control the MSR and clonus after SCI, we examined how serotonin regulates the MSR in the sacrocaudal spinal cord of rats with and without a chronic spinal transection. In chronic spinal rats, numerous 5-HT receptor agonists, including zolmitriptan, methylergonovine, and 5-HT, inhibited the MSR with a potency highly correlated to their binding affinity to 5-HT<jats:sub>1D<\/jats:sub>receptors and not other 5-HT receptors. Selective 5-HT<jats:sub>1D<\/jats:sub>receptor antagonists blocked this agonist-induced inhibition, although antagonists alone had no action, indicating a lack of endogenous or constitutive receptor activity. In normal uninjured rats, the MSR was likewise inhibited by 5-HT, but at much higher doses, indicating a supersensitivity after SCI. This supersensitivity resulted from the loss of the serotonin transporter SERT with spinal transection, because normal and injured rats were equally sensitive to 5-HT after SERT was blocked or to agonists not transported by SERT (zolmitriptan). Immunolabeling revealed that the 5-HT<jats:sub>1D<\/jats:sub>receptor was confined to superficial lamina of the dorsal horn, colocalized with CGRP-positive C-fibers, and eliminated by dorsal rhizotomy. 5-HT<jats:sub>1D<\/jats:sub>receptor labeling was not found on large proprioceptive afferents or \u03b1-motoneurons of the MSR. Thus serotonergic inhibition of the MSR acts indirectly by modulating C-fiber activity, opening up new possibilities for modulating reflex function and clonus via pain-related pathways.<\/jats:p><jats:p>NEW &amp; NOTEWORTHY Brain stem-derived serotonin potently inhibits afferent transmission in the monosynaptic stretch reflex. We show that serotonin produces this inhibition exclusively via 5-HT<jats:sub>1D<\/jats:sub>receptors, and yet these receptors are paradoxically mostly confined to C-fibers. This suggests that serotonin acts by gating of C-fiber activity, which in turn modulates afferent transmission to motoneurons. We also show that the classic supersensitivity to 5-HT after spinal cord injury results from a loss of SERT, and not 5-HT<jats:sub>1D<\/jats:sub>receptor plasticity.<\/jats:p>","DOI":"10.1152\/jn.00805.2018","type":"journal-article","created":{"date-parts":[[2019,1,9]],"date-time":"2019-01-09T20:17:25Z","timestamp":1547065045000},"page":"1591-1608","source":"Crossref","is-referenced-by-count":24,"title":["5-HT<sub>1D<\/sub>receptors inhibit the monosynaptic stretch reflex by modulating C-fiber activity"],"prefix":"10.1152","volume":"121","author":[{"given":"Ana M.","family":"Lucas-Osma","sequence":"first","affiliation":[{"name":"Neuroscience and Mental Health Institute and Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqing","family":"Li","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute and Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Murray","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute and Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihao","family":"Lin","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute and Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Black","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute and Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilee J.","family":"Stephens","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute and Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew H.","family":"Ahn","sequence":"additional","affiliation":[{"name":"Teva Pharmaceuticals, Clinical Development, North Wales, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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