Journal
PAIN
Volume 160, Issue 1, Pages 136-150Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/j.pain.0000000000001386
Keywords
Cannabidiol; Pain; Dorsal raphe; Electrophysiology; Anxiety
Categories
Funding
- Ministere de l'Economie Science et Innovation du Quebec (MESI, Program PSR-SIIRI)
- Aurora Cannabis Inc.
- Fonds de la recherche du Quebec en Sante (FRQS)
- Louise and Alan Edwards Foundation
- Quebec Merit Scholarship
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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-Him antagonist WAY 100635 (0.3 mg/kg, i.v.) and the TRW, antagonist capc7epine (1 mg/kg, i.v.) but not by the CB, receptor antagonist AM 251 (1 mg/kg, i.v.). Repeated treatment with CBD (5 m g/kg/day, subcutaneously [s.c.], for 7 days) increased 5-HT1A firing through desensitization of 5-HT1A receptors. Rats subjected to the spared nerve injury model for 24 days showed decreased 5HT firing activity, mechanical allodynia, and increased anxiety-like behavior in the elevated plus maze test, open-field test, and noveltysuppressed feeding test. Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-I-IT activity. Antiallodynic effects of CBD were fully prevented by capganpine (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.
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