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Evaluating naturally-derived cannabis combinations and conopeptides in a rat SCI pain model

Yousra Erritouni
University of Miami

Co-Authors: Anjalika Eeswara1, Kristin Perrucci1, Stanislava Jergova1, Jacqueline Sagen1
1University of Miami

Chronic neuropathic pain resulting from spinal cord injury (SCI) is often difficult to treat, as most available therapies are associated with undesirable side effects or are only modestly effective. Activation of cannabinoid receptors have been known to regulate pain responses. Cannabinoid receptor 1 (CB1) in particular is found throughout the CNS and is a promising target for attenuating neuropathic pain. As such, we looked at two sources of CB receptor agonists, plant-derived cannabis constituents and Conus venoms, for SCI pain. For phytocannabanoids, we explored combinations of cannabidiol (CBD) and β-caryophyllene (BCP), as neither is associated with psychoactive side effects. The venom of marine snail genus Conus is a natural source of various peptides with potent antinociceptive activity. We screened several Conus venoms for their ability to induce CB1 receptor internalization and chose C. Textile venom samples as the best candidate to search for CB1 receptor ligands.

​The analgesic properties of CBD, BCP and their combination in a rat SCI clip model, and their in vitro CB1 receptor activity were tested. Animals were treated with CBD, BCP and CBD/BCP combination at various doses and evaluated for mechanical and thermal hypersensitivity. Analgesic effects were observed for drug combinations at lower doses than that of single drug administration suggesting synergism. The effect of CBD/BCP was blocked by CB1 antagonist AM251, but not by CB2 antagonist AM630. Treatment of cells expressing CB1 and CB2 receptors in an internalization assay showed minimal effect of single treatment on either receptor. The combination of CBD/BCP showed significant activity at CB1 receptors and enhanced activity at CB2 receptors compared to individual treatments, and was reduced by AM251 and AM630. In a separate cohort of SCI animals C. textile venom sub-fractions with the highest CB1 agonist activity were evaluated in animals after a single intrathecal injection or after prolonged delivery by Alzet pumps. Screening of these samples identified at least two cannabinoid acting peptidergic fractions that may have promise in further development towards therapeutics for the management of chronic pain. Our results suggest that compounds targeting the CB1 receptor may prove beneficial in the management of neuropathic pain.

Funding through the 2019 Research Grants Program of the Consortium for Medical Marijuana Clinical Outcomes Research through State of Florida appropriations and Department of Defense (CDMRP SCIRP SC170295).

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