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

Affiliations

  • 1 Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, QC, Canada.
  • 2 Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, United States.
  • 3 Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
  • 4 Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania “Luigi Vanvitelli,” Naples, Italy.
  • 5 Division of Neuroscience, San Raffaele Scientific Institute and Vita Salute University, Milan, Italy.
  • PMID: 30157131
  • PMCID: PMC6319597
  • DOI: 10.1097/j.pain.0000000000001386

Free PMC article

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

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Authors

Affiliations

  • 1 Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, QC, Canada.
  • 2 Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, United States.
  • 3 Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
  • 4 Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania “Luigi Vanvitelli,” Naples, Italy.
  • 5 Division of Neuroscience, San Raffaele Scientific Institute and Vita Salute University, Milan, Italy.
  • PMID: 30157131
  • PMCID: PMC6319597
  • DOI: 10.1097/j.pain.0000000000001386

Abstract

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.

Conflict of interest statement

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

Figures

Acute and repeated CBD administration…

Acute and repeated CBD administration on firing activity of DRN 5-HT neurons in…

Repeated CBD treatment increases paw…

Repeated CBD treatment increases paw withdrawal threshold and prevents anxiety-like behavior in the…

TRPV 1 antagonism blocked the…

TRPV 1 antagonism blocked the antinociceptive, but not the anxiolytic effects, of repeated…

5-HT 1A antagonism partially prevented…

5-HT 1A antagonism partially prevented antinociception and completely blocked the anxiolytic properties of…

Repeated CBD treatment prevents SNI-induced…

Repeated CBD treatment prevents SNI-induced alterations in DRN 5-HT neuronal activity. (A) Mean…

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 …