Cannabinoids for Neuropathic Pain

Abstract

Neuropathic pain is a severe chronic syndrome and is poorly served by current pharmacotherapeutics. There is some evidence that the cannabis constituents tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination relieves neuropathic pain. However, there is little to no animal evidence for their effectiveness and side effects in neuropathic pain models. In this thesis, a systematic analysis of THC and CBD was performed in a mouse neuropathic pain model. Systemic subcutaneous and oral THC had high anti-allodynic efficacy, but was accompanied by side effects. By contrast, CBD had lower anti-allodynic efficacy, but lacked side effects. Isobolographic analysis demonstrated synergistic analgesia for combination THC and CBD for subcutaneous but not oral administration. Thus, combination THC:CBD had a high therapeutic window when delivered subcutaneously but not orally. Finally, both THC and CBD produced high efficacy anti-allodynia without side effects administered via intrathecal or intraplantar injection. The actions of THC were mostly cannabinoid CB1 receptor mediated, while the actions of CBD were not cannabinoid receptor mediated. An in vitro electrophysiological identified potential cannabinoid targets in sensory neurons. Activity at T-type calcium currents, but not other calcium currents or tetrodotoxin-resistant sodium currents, may account for some of the anti-allodynic activity of THC and CBD. Overall, this thesis provides pre-clinical evidence that the phytocannabinoids THC and CBD alone may be useful as an adjunct therapy for treatment of neuropathic pain, and provides insight as to the ideal ratio and differing benefits and challenges of different administration routes. It also provides some insight into the cellular mechanisms of activity of these phytocannabinoids.