Project Grant F31DA066087

EFFECTS OF CANNABINOIDS ON ENDOCANNABINOID REGULATION, SENSORY PROCESSING, AND PAIN NEUROBIOLOGY IN KNEE OSTEOARTHRITIS - PROJECT SUMMARY THE INTERSECTION OF THE OPIOID EPIDEMIC AND WIDESPREAD CANNABIS LEGALIZATION HAS DIRECTED ATTENTION TOWARD CANNABIS AS A PROMISING TREATMENT FOR CHRONIC PAIN, INCLUDING KNEE OSTEOARTHRITIS (OA). CANNABIS COMPOUNDS, PARTICULARLY D9-TETRAHYDROCANNABINOL (THC) AND CANNABIDIOL (CBD), ACT ON THE ENDOGENOUS CANNABINOID (ECB) SYSTEM, WHICH IS INVOLVED IN PAIN PROCESSING AT PERIPHERAL, SPINAL, AND SUPRASPINAL LEVELS. DESPITE APPROXIMATELY 30% OF INDIVIDUALS WITH CHRONIC PAIN RESORTING TO CANNABIS FOR RELIEF, THE CONTRIBUTIONS OF ECBS AND THEIR INTERACTIONS WITH EXOGENOUS CANNABINOIDS, SUCH AS THC AND CBD, REMAIN POORLY UNDERSTOOD. WE PROPOSE TO CONDUCT SECONDARY ANALYSES OF AN NIH-FUNDED, 2X2 FACTORIAL, DOUBLE-BLIND CLINICAL TRIAL INVOLVING KNEE OA PATIENTS RANDOMIZED TO RECEIVE CBD, THC, BOTH, OR PLACEBO. THIS TRIAL CAPTURES CIRCULATING ECB CONCENTRATIONS MULTIPLE TIMES DURING TREATMENT, AS WELL AS QUANTITATIVE SENSORY TESTING (QST) DATA, PATIENT- REPORTED OUTCOMES (PROS), AND FUNCTIONAL NEUROIMAGING (FMRI) AT BASELINE AND AFTER TREATMENT. THE GOAL OF THIS F31 IS TO CHARACTERIZE THE INFLUENCE OF EXOGENOUS CANNABINOID TREATMENT ON THE ECB SYSTEM IN PATIENTS WITH PAINFUL KNEE OA. IN AIM 1, WE WILL CHARACTERIZE THE RELATIONSHIP BETWEEN CIRCULATING ECB CONCENTRATIONS AND CLINICAL PAIN OUTCOMES (E.G., PAIN INTENSITY) OVER THE COURSE OF CANNABINOID TREATMENT. WE HYPOTHESIZE THAT ECB CONCENTRATIONS WILL DECREASE FOLLOWING CANNABINOID TREATMENT COMPARED TO PLACEBO, AND THESE REDUCTIONS WILL BE ASSOCIATED WITH REDUCTIONS IN CLINICAL PAIN OUTCOMES AFTER CANNABINOID TREATMENT RELATIVE TO PLACEBO. AIM 2 WILL UTILIZE QST TO CHARACTERIZE THE RELATIONSHIP BETWEEN CIRCULATING ECB CONCENTRATIONS AND MULTIMODAL SENSORY RESPONSES. WE HYPOTHESIZE A POSITIVE BASELINE CORRELATION BETWEEN MULTIMODAL SENSORY SENSITIVITY AND ECB CONCENTRATIONS, AND THAT DECREASES IN ECB CONCENTRATIONS WITH CANNABINOID TREATMENT WILL PREDICT CORRESPONDING REDUCTIONS IN SENSORY SENSITIVITY. LASTLY, AIM 3 WILL CHARACTERIZE THE RELATIONSHIP BETWEEN CIRCULATING ECB CONCENTRATIONS AND PAIN NEUROBIOLOGY. WE HYPOTHESIZE THAT REDUCTIONS IN NEURAL ACTIVATION IN PAIN-RELATED AREAS (E.G., INSULA, PRIMARY SOMATOSENSORY CORTEX, AND THALAMUS) WITH EXOGENOUS CANNABINOID TREATMENT WILL BE ASSOCIATED WITH A REDUCTION IN ECB CONCENTRATIONS. I WILL RECEIVE TRAINING IN PAIN SCIENCE, THE ECB SYSTEM IN THE CONTEXT OF CHRONIC PAIN, NEUROIMAGING TECHNIQUES, CANNABINOID THERAPEUTICS. THIS RESEARCH, BY CLARIFYING THE ECB SYSTEM'S ROLE AND ITS MODULATION THROUGH CANNABINOID TREATMENTS, SEEKS TO LAY THE GROUNDWORK FOR DEVELOPING MECHANISM-BASED, INDIVIDUALIZED PAIN MANAGEMENT STRATEGIES, SIGNIFICANTLY ADVANCING CHRONIC PAIN THERAPEUTICS AND POTENTIALLY IMPROVING PATIENT OUTCOMES. IN ADDITION, THIS STUDY AND TRAINING WILL FACILITATE MY LONG-TERM CAREER GOAL TO BECOME AN INDEPENDENT RESEARCHER WITH A RESEARCH PROGRAM FOCUSED ON INVESTIGATING THE NEUROBIOLOGICAL MECHANISMS OF CHRONIC PAIN AND UNDERSTANDING THE ENDOCANNABINOID SYSTEM IN THE CONTEXT OF CHRONIC PAIN.