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2022: Evaluation of Cannabis constituents in a model of phantom limb pain in rats

Anjalika Eeswara
University of Miami

Co-authors: Amanda Pacheco-Spiewak1, Stanislava Jergova1, Jacqueline Sagen1
1University of Miami

Objective: Phantom Limb Pain (PLP) often results from medically required limb amputation and becomes difficult to manage due to underlying inflammation and other neuropathologies, affecting up to 85% of amputees. Medical marijuana is often used for pain relief and may be beneficial for chronic pain syndromes like PLP due to the wealth of cannabinoid (CB) compounds acting via distinct or synergistic mechanisms. The goal of this study was to evaluate the analgesic potential of delta-9tetrahydrocannabinol (THC), Cannabidiol (CBD), β-caryophyllene (BCP) and their combination in preventing or reversing PLP-like behavior.

Methods: Using male Sprague-Dawley rats, complete sciatic nerve transection was used to replicate limb amputation. To model complex limb injuries leading to medically-indication amputation, first chronic constriction injury (CCI) was induced using chromic gut ligatures placed around the sciatic nerve. One week later intraplantar formalin was injected 2 hours prior to performing complete axotomy. To assess for PLP, animals were observed daily using a scale designed to capture and distinguish overall autotomy severity. Based on previous studies in our lab that established optimal synergistic CBD:BCP doses, animals were injected twice daily with either THC, CBD:BCP or THC:CBD:BCP at the following doses: 0.04 mg/kg THC, 2.0 mg/kg CBD and 16.0 mg/kg BCP. Animals were sacrificed when proximal injury appeared, with the day of termination recorded, or by 72 days post-axotomy.

Results: Administration of all of the tested cannabis combinations showed attenuation in the severity and onset of PLP-like behaviors compared to the vehicle controls. Comparison between experimental groups showed that animals treated with either THC alone or CBD:BCP combination displayed lower autotomy scores compared to animals receiving all three together (THC:CBD:BCP). This may be due to competing partial agonist effects of one or more of the components, and will be further investigated. No overt side effects were observed following any treatments.

Conclusion: These findings further support the novel use of cannabis constituents as therapeutic agents for the management of neuropathic pain syndromes. In particular, identification of effective combinations of mechanistically distinct cannabis components may be beneficial in preventing the development of debilitating and difficult-to-treat phantom limb pain.

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