Targeting the endocannabinoid (eCB) signaling system for pain relief is an important treatment option that is only now beginning to be mechanistically explored. In this review, we focus on two recently appreciated cannabinoid-based targeting strategies, treatments with cannabidiol (CBD) and α/β-hydrolase domain containing 6 (ABHD6) inhibitors, which have the exciting potential to produce pain relief through distinct mechanisms of action and without intoxication. We review evidence on plant-derived cannabinoids for pain, with an emphasis on CBD and its multiple molecular targets expressed in pain pathways. We also discuss the function of eCB signaling in regulating pain responses and the therapeutic promises of inhibitors targeting ABHD6, a 2-arachidonoylglycerol (2-AG)-hydrolyzing enzyme. Finally, we discuss how the novel cannabinoid biosensor GRABeCB2.0 may be leveraged to enable the discovery of targets modulated by cannabinoids at a circuit-specific level.

SIGNIFICANCE STATEMENT Cannabis has been used by humans as an effective medicine for millennia, including for pain management. Recent evidence emphasizes the therapeutic potential of compounds that modulate endocannabinoid signaling. Specifically, cannabidiol and inhibitors of the enzyme ABHD6 represent promising strategies to achieve pain relief by modulating endocannabinoid signaling in pain pathways via distinct, nonintoxicating mechanisms of action.

This work was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS118130] (to N.S.); National Institute on Drug Abuse [Grant DA047626] (to N.S.), [Grant DA033396] (to M.R.B.), [Grant AT011524] (to B.B.L.), and [Grant 5T32DA007278-30] (to K.J.E.); and National Institute of General Medical Sciences [Grant T32GM007750] (to S.S.). This work was also supported by the University of Washington Center of Excellence in Opioid Addiction Research/Molecular Genetics Resource Core [Grant P30DA048736].

No author has an actual or perceived conflict of interest with the contents of this article.

↵1 B.B.L. and N.S. contributed equally to this work as last authors.

dx.doi.org/10.1124/jpet.124.002119.