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Cannabis constituent synergy in a mouse neuropathic pain model

Casey, Sherelle L.*; Atwal, Nicholas; Vaughan, Christopher W.

doi: 10.1097/j.pain.0000000000001051
Research Paper
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Cannabis and its psychoactive constituent Δ9-tetrahydrocannabinol (THC) have efficacy against neuropathic pain, however, this is hampered by their side effects. It has been suggested that co-administration with another major constituent cannabidiol (CBD) might enhance the analgesic actions of THC and minimise its deleterious side effects. We examined the basis for this phytocannabinoid interaction in a mouse chronic constriction injury (CCI) model of neuropathic pain. Acute systemic administration of THC dose-dependently reduced CCI-induced mechanical and cold allodynia, but also produced motor incoordination, catalepsy, and sedation. Cannabidiol produced a lesser dose-dependent reduction in allodynia, but did not produce the cannabinoid side effects. When co-administered in a fixed ratio, THC and CBD produced a biphasic dose-dependent reduction in allodynia. At low doses, the THC:CBD combination displayed a 200-fold increase in anti-allodynic potency, but had lower efficacy compared with that predicted for an additive drug interaction. By contrast, high THC:CBD doses had lower potency, but greater anti-allodynic efficacy compared with that predicted for an additive interaction. Only the high dose THC:CBD anti-allodynia was associated with cannabinoid side effects and these were similar to those of THC alone. Unlike THC, the low dose THC:CBD anti-allodynia was not cannabinoid receptor mediated. These findings demonstrate that CBD synergistically enhances the pain-relieving actions of THC in an animal neuropathic pain model, but has little impact on the THC-induced side effects. This suggests that low dose THC:CBD combination treatment has potential in the treatment of neuropathic pain.

Combination treatment with the phytocannabinoids THC and cannabidiol synergistically reduces allodynia in a neuropathic pain model. The observed drug interaction proffers 2 divergent treatment regimes.

Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales, Australia

Corresponding author. Address: Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW 2065, Australia. Tel.: 61(2)9926 4963. E-mail address: scas5381@uni.sydney.edu.au (S. L. Casey).

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

Received June 07, 2017

Received in revised form July 26, 2017

Accepted August 21, 2017

© 2017 International Association for the Study of Pain
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