Project Grant F31DA061576

INVESTIGATING THE ROLE OF THC IN MEDIATING PAIN SIGNALING IN THE BLA - PROJECT SUMMARY CHRONIC PAIN AFFECTS BETWEEN 40 TO 100 MILLION PEOPLE IN THE US AND MANAGING THIS PAIN WITH OPIOIDS HAS INCREASED THE INCIDENCE OF OPIOID SUBSTANCE ABUSE AND DEATH FROM OVERDOSE. THERE IS AN URGENT AND UNMET NEED FOR EFFECTIVE CHRONIC PAIN MEDICATIONS WITH LOWER MISUSE POTENTIAL. Δ9-TETRAHYDROCANNABINOL (THC) IS THE MOST ABUNDANT PHARMACOLOGICAL AGENT FOUND WITHIN CANNABIS AND ACTS VIA THE ENDOCANNABINOID (ECB) SIGNALING SYSTEM TO PRODUCE ANALGESIA. THIRTY-EIGHT US STATES HAVE APPROVED LEGAL MEDICAL CANNABIS FOR THE PHARMACOLOGICAL TREATMENT OF PAIN AND ANXIETY, ALONGSIDE RECREATIONAL USE IN MANY CASES. HOWEVER, THE PRECISE NEUROPHARMACOLOGICAL AND PHYSIOLOGICAL MECHANISMS OF THC USE FOR PAIN TREATMENT, AND THE CIRCUIT MECHANISMS THAT UNDERLIE THE PAIN-RELIEVING PROPERTIES OF THC ARE UNKNOWN. THE BASOLATERAL AMYGDALA (BLA) IS A CRITICAL BRAIN REGION IMPORTANT FOR ENCODING AFFECTIVE INFORMATION FROM INCOMING STIMULI AND IS A KEY COMPONENT IN PAIN PROCESSING. THE BLA HAS INCREASED NEURONAL ACTIVITY DURING CHRONIC PAIN, AND GLUTAMATERGIC NEURONAL ENSEMBLES DETECT AND REPORT NOXIOUS STIMULI TO CORTICAL STRUCTURES THAT IMPACT PAIN PERCEPTION. THE BLA HAS ENRICHED EXPRESSION OF THE RECEPTOR SENSITIVE TO ECBS AND THC, CANNABINOID 1 RECEPTOR (CB1R). THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT THC ACTS AS A PARTIAL AGONIST AT CB1R TO DECREASE EXCITATORY BLA NEURONAL ACTIVITY AND PAIN BEHAVIORS DURING CHRONIC PAIN. THIS PROPOSAL DIRECTLY ADDRESSES THE 2022-2026 NIDA STRATEGIC PLAN GOAL 1.1 TO, "EXPAND OUR UNDERSTANDING OF THE BIOLOGICAL MECHANISMS UNDERLYING DRUG USE, ADDICTION, DIVERSE TREATMENT RESPONSES..." AND THE NINDS 2021-2026 STRATEGIC PLAN TO"... EXTEND PROGRESS IN PREVENTION FOR NEUROLOGICAL DISEASES BEYOND STROKE, BUILDING ON BASIC RESEARCH ADVANCES IN EPILEPSY, TBI, NEURODEGENERATIVE DISEASES, CHRONIC PAIN..." AIM 1 WILL DETERMINE WHETHER THC ACTS WITHIN THE BLA AT CB1RS TO ALTER GLUTAMATERGIC NEURONAL ACTIVITY TO PROMOTE ANALGESIA DURING CHRONIC PAIN. IN THIS AIM, WE WILL MULTIPLEX CLASSIC NEUROPHARMACOLOGY AND DUAL-COLOR FIBER PHOTOMETRY WITH A MACHINE LEARNING-BASED BEHAVIORAL TRACKING PLATFORM TO DIRECTLY CORRELATE LOCAL THC-ACTION AND NEURAL ACTIVITY WITH NATURALISTIC CHRONIC PAIN BEHAVIORS. WE THEN PROPOSE IN AIM 2 TO DECODE HOW AND WHERE THC ALTERS SPECIFIC BLAGLU NEURONAL ENSEMBLE ACTIVITY DURING CHRONIC PAIN. WE WILL USE IN VIVO 2-PHOTON CALCIUM IMAGING, A CRISPR SITE-SPECIFIC CB1R DELETION STRATEGY, AND A HEAD-FIXED BEHAVIORAL PARADIGM TO OBSERVE GLUTAMATERGIC BLA NEURONAL ENSEMBLES DURING PAIN. THESE FINDINGS WILL PROVIDE FOUNDATIONAL KNOWLEDGE INFORMING THE CANNABINOID, SUBSTANCE ABUSE, NEUROPHARMACOLOGY, AND PAIN FIELDS. FOR THIS PROPOSAL, I WILL GAIN TRAINING AND EXPERTISE IN THE USE OF PHARMACOLOGICAL, NOVEL BIOLOGICAL AND HIGH RESOLUTION COMPUTATIONAL TECHNIQUES AND LEARN VALUABLE CAREER DEVELOPMENT SKILLS THROUGH A WIDE VARIETY OF SCIENTIFIC, INTELLECTUAL, AND MENTORED OPPORTUNITIES. THIS F31 PROPOSAL IS SPECIFICALLY TAILORED TO MY PERSONAL TRAINING NEEDS AND CAREER ASPIRATIONS THAT WILL PREPARE ME FOR A CAREER AS AN INDEPENDENT ACADEMIC NEUROPHARMACOLOGIST.