FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R2682.
Despite decades of research examining the biological mechanisms of pain, few new treatments have been developed. Cannabis has been used for centuries to treat pain, and previous evidence indicates that non-∆9-tetrahydrocannabinol and non-cannabidiol constituents of Cannabis can produce pain relief in animal models. The Cannabis-related terpene ß-caryophyllene (BCP) produces pain relief in various pain tests with varying degrees of efficacy; however, the pharmacological mechanism underlying this pain relief is unclear. Previous studies by other groups have demonstrated that BCP produces antinociception via cannabinoid and opioid mechanisms following local administration into the hindpaw. As such, we hypothesized that BCP produces analgesia via opioid mechanisms following systemic administration. To test this hypothesis, we administered varying doses of BCP and evaluated their antinociceptive effects on the hot plate and tail-flick tests in adult male Sprague-Dawley rats. The hot plate test identifies pain relief mediated by supraspinal mechanisms. The tail-flick test identifies pain relief mediated by spinal mechanisms. One intraperitoneal injection of 30 mg/kg BCP produced antinociception on the hot plate test and the tail-flick test approximately 15 minutes after injection. Vehicle and doses of 3 mg/kg and 10 mg/kg were ineffective at producing pain relief on the hot plate and tail-flick tests. In order to test the contribution of opioid receptors, a subset of rats received a 30 min pretreatment of the opioid receptor antagonist naltrexone. The effect of naltrexone on BCP-induced antinociception varied depending on both dose and time. These results indicate that low doses of BCP may effectively alleviate acute pain and that BCP-induced antinociception may be mediated, in part, by opioid receptors. Further studies are needed to fully understand the relationship between BCP and opioid receptors to determine their therapeutic potential.