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.
1
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal (QC), Canada.
2
Equal author contribution.
3
Department of Integrative Physiology and Neuroscience, Washington State University, Pullman (WA) USA.
4
Alan Edwards Centre for Research on Pain, McGill University, Montreal (QC), Canada.
5
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
6
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. |
