Analgesic potential of novel peripherally-restricted CB1 ligands - Project Summary Preclinical studies that have shown significant analgesic efficacy of targeting peripheral cannabinoid type 1 receptors (CB1Rs) in diverse pain models contrast with disappointing results from clinical studies where the analgesic efficacy of targeting CB1Rs, including using peripherally selective compounds, has been inconsistent. This discrepancy likely results from a number of addressable issues that we will resolve in this proposal. Perhaps cannabinoid therapeutics tested in humans to date do not sufficiently activate CB1R in the periphery. Inadequate peripheral restriction has hampered prior clinical trials of purported “peripherally restricted” cannabinoids. Partitioning of these compounds into the brain leads to dose limiting psychoactivity. We recently developed VIP36, a novel CB1R agonist that shows robust analgesic actions and dramatically improved peripheral restriction. The improved peripheral selectivity of VIP36 will allow maximal activation of peripheral CB1R without psychoactivity associated with CB1R activation in the brain. Perhaps the way we have done preclinical testing in animals is not predictive of efficacy in humans. In Aim 1 of this application, we test the efficacy of VIP36 in mouse models of post-traumatic headache, post- operative pain, and a new model of nerve injury-induced pain. These models have improved face validity for human clinical pain. We also use behavioral endpoints that assess affective-motivational aspects of pain, which will enhance preclinical validation and provide greater predictive power for utility in humans. Perhaps there are differences in CB1R expression or function between rodents and humans. In Aim 2, we will test whether CB1R is expressed in similar cell populations in dorsal root ganglia (DRG) and trigeminal ganglia in mice and humans. We will also test whether CB1R activation has similar functional effects in mouse and human DRG neurons using electrophysiology. Perhaps prior cannabis exposure blunts analgesic efficacy of CB1R ligands in humans. Frequent cannabis use leads to downregulation of CB1R in human brain. This could lead to reduced efficacy of cannabinoid analgesics. Given the widespread recreational and medical use of cannabis, it is conceivable that CB1R downregulation or tolerance in participants of clinical trials could confound results. In Aim 3, we test whether a history of frequent THC exposure leads to cross-tolerance to analgesic effects of THC and VIP36. We also ask whether frequent THC exposure leads to reduced CB1R expression in dorsal root ganglia (DRG) and trigeminal ganglia in mouse models and in DRG recovered from human organ donors with a history of daily cannabis use. Collectively, our approach is designed to evaluate the potential analgesic efficacy of peripherally restricted CB1R agonists and obtain data that will either support or refute the notion that this is likely to translate effectively to humans. The proposed studies will also significantly advance our understanding of human cannabinoid receptor biology.
