|Pain. 2018 Aug 27. doi: 10.1097/j.pain.0000000000001386. [Epub ahead of print]|
Cannabidiol modulates serotonergic transmission and prevents allodynia and anxiety-like behavior in a model of neuropathic pain.
De Gregorio D1,2, McLaughlin RJ3,2, Posa L1,4, Ochoa-Sanchez R1, Enns J1, Lopez-Canul M1, Aboud M1, Maione S5, Comai S1,6, Gobbi G1,4.
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal (QC), Canada.
Equal author contribution.
Department of Integrative Physiology and Neuroscience, Washington State University, Pullman (WA) USA.
Alan Edwards Centre for Research on Pain, McGill University, Montreal (QC), Canada.
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
San Raffaele Scientific Institute and Vita Salute University, Milan, Italy.
Clinical studies indicate that cannabidiol (CBD), the primary non-addictive component of cannabis that interacts with the serotonin (5-HT) 1A receptor, may possess analgesic and anxiolytic effects. However, its effects on 5-HT neuronal activity, as well as its impact in models of neuropathic pain are unknown. First, using in-vivo single unit extracellular recordings in rats, we demonstrated that acute intravenous (i.v.) increasing doses of CBD (0.1-1.0 mg/kg) decreased the firing rate of 5-HT neurons in the dorsal raphe nucleus (DRN), which was prevented by administration of the 5-HT1A antagonist WAY 100635 (0.3 mg/kg, i.v.) and the TRPV1 antagonist capsazepine (1 mg/kg, i.v.) but not by the CB1 receptor antagonist AM 251 (1 mg/kg, i.v.). Repeated treatment with CBD (5 mg/kg/day, subcutaneously, s.c, for 7 days) increased 5-HT firing via desensitization of 5-HT1A receptors. Rats subjected to the spared nerve injury (SNI) model for 24 days showed decreased 5-HT firing activity, mechanical allodynia, and increased anxiety-like behavior in the elevated plus maze (EPMT), open field (OFT), and novelty suppressed feeding tests (NSFT). Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity. Anti-allodynic effects of CBD were fully prevented by capsazepine (10 mg/kg/day, s.c., for 7 days) and partially prevented by WAY 100635 (2 mg/kg/day, s.c., for 7 days), while the anxiolytic effect was blocked only by WAY. Overall, repeated treatment with low-dose CBD induces analgesia predominantly via TRPV1 activation, reduces anxiety via 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.