Elucidating interplay between myrcene and cannabinoid receptor 1 receptors to produce antinociception in mouse models of neuropathic pain

The need for nonaddictive and effective treatments for chronic pain are at an all-time high. Historical precedence, and now clinical evidence, supports the use of cannabis for alleviating chronic pain. A plethora of research on delta-9-tetrahydrocannabinol exists, yet cannabis is comprised of a multitude of constituents, some of which possess analgesic potential, that have not been systematically investigated, including the terpene myrcene. Myrcene attenuates pain hypersensitivity in preclinical models and is one of the most abundant terpenes found in cannabis. Despite these findings, it remains unclear how myrcene elicits these effects on nociceptive systems. The present study uses a male and female mouse model of neuropathic pain as well as in vitro experiments with HEK293T cells to explore these questions. We first demonstrate myrcene (1-200 mg/kg i.p.) dose-dependently increases mechanical nociceptive thresholds, where potency was greater in female compared with male pain mice. Testing canonical tetrad outcomes, mice were tested for hypolocomotion and hypothermia after myrcene administration. Myrcene did not alter locomotion or temperature, but female pain mice showed a conditioned place aversion to myrcene. A cannabinoid receptor 1 (CB1) antagonist inhibited myrcene's anti-allodynia. By contrast, in vitro cell culture experiments using a TRUPATH assay revealed myrcene does not directly activate CB1 receptors nor alter CB1 receptor activity elicited by CB1 agonist (CP 55,940) or endocannabinoids (anandamide or 2-arachidonoylglycerol). Understanding engagement of CB1 receptors in pain modulation and myrcene's mechanism of action warrants further study to understand the diversity of cannabis pharmacology and to further the frontier of pain research.