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Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain

De Gregorio, Daniloa; McLaughlin, Ryan J.b; Posa, Lucaa,c; Ochoa-Sanchez, Rafaela; Enns, Justinea; Lopez-Canul, Marthaa; Aboud, Matthewa; Maione, Sabatinod; Comai, Stefanoa,e; Gobbi, Gabriellaa,c,*

doi: 10.1097/j.pain.0000000000001386
Research Paper: PDF Only

Clinical studies indicate that cannabidiol (CBD), the primary nonaddictive 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 on 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, 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 through desensitization of 5-HT1A receptors. Rats subjected to the spared nerve injury model for 24 days showed decreased 5-HT firing activity, mechanical allodynia, and increased anxiety-like behavior in the elevated plus maze test, open-field test, and novelty-suppressed feeding test. Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity. Antiallodynic 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), whereas the anxiolytic effect was blocked only by WAY. Overall, repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.

Low dose of cannabidiol ameliorates mechanical allodynia and anxious behavior and restores impaired serotonergic transmission in a neuropathic pain model in rats.

aNeurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, QC, Canada

bDepartment of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, United States

cAlan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada

dDepartment of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania “Luigi Vanvitelli,” Naples, Italy

eDivision of Neuroscience, San Raffaele Scientific Institute and Vita Salute University, Milan, Italy

Corresponding author. Address: Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Room 220, Irving Ludmer Psychiatry Research and Training Building, 1033 Pine Ave West, McGill University, Montreal, PQ H3A 1A1, Canada. Tel.: +1-514-398-1290; fax: +1-514-398-4866. E-mail address: gabriella.gobbi@mcgill.ca (G. Gobbi).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

D. De Gregorio and R.J. McLaughlin contributed equally to this work.

Received March 19, 2018

Accepted August 02, 2018

© 2018 International Association for the Study of Pain
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