INVESTIGATOR: Catherine Cahill, Ph.D.

STUDY LOCATION: UCLA

PROJECT TITLE: Myrcene modulates on CB1 receptor function via enhancement of endocannabinoids

FUNDING SOURCE: Center for Medicinal Cannabis Research

PROJECT TYPE: Pre-Clinical Study

STATUS: Active

ABSTRACT:

Cannabinoids and terpenes derived from the cannabis plant hold promise as novel pharmacotherapeutics to reduce reliance on opioids for pain management. While delta-9-tetrahydrocannabinol (THC) and cannabidiol have been primary targets for understanding the therapeutic effects of cannabis, accumulating evidence suggests that terpenes, non-intoxicating constituents of the cannabis plant, play an important role in reducing pain. Myrcene is one the most abundant terpenes found in medical cannabis, and rodent studies, including our own, suggest that it has analgesic potential. Importantly, the effects of these terpenes are noticeable to uses and likely contribute to the ‘entourage’ effect that enhances the effects of THC; where clinical trials showed that THC alone was not better than placebo. The endocannabinoid system is comprised of two G-protein coupled receptors (CB1 and CB2) that are activated by endogenous ligands 2-arachidonoylglycerol and anandamide. Terpene-induced antinociception is blocked by CB1 or CB2 antagonists, but some studies suggest that it does not bind to the CB receptors. This proposal will test the hypothesis that terpenes enhance endocannabinoid concentrations in the periaqueductal gray, a brain region important in modulating nociception but have no direct effect on CB receptor signaling. Recent advancement in photometric sensor technology allowed for the development of GRABeCB2.0, a fluorescent sensor providing a sharp spatiotemporally measure of endocannabinoid dynamics in vivo. Using this approach over traditional LC/MS techniques allows us to monitor and investigate time-locked endogenous cannabinoid signaling and behavioral outcomes with a high level of granularity. We will study a projection from the lateral hypothalamus to the ventrolateral PAG that is involved in antinociception that is blocked by CB receptor but not opioid receptor antagonists. We will complement this in vivo data using imaging and BRET based assays to examine activation of different G protein subtypes. Currently, we will use the BRET-based TRUPATH assay to determine the potential for myrcene to directly activate CB receptors. Data generated with this proposal will provide strong evidence for that terpenes engage endocannabinoids and inform mechanisms and circuits by which they produce their effects. It will also provide a premise for additional competitive national funding opportunities. All data will be analyzed by Factorial ANOVA analyses.