ABSTRACT Chronic pain is a serious and worsening epidemic in the United States and worldwide seriouslydegrading patient quality of life. Opioid drugs like morphine are the gold standard for treating moderate tosevere chronic pain however they are burdened by major side effects especially addiction liability which hascontributed to a paralell epidemic of opioid addiction abuse and overdose. In addition opioids are ineffective insome pain types most notably neuropathic pain. In the search for alternatives phytocannabinoids from Cannabissativa have been heavily studied. However cannabinoids have generally been shown to have modest to poorefficacy and have their own side effects especially psychoactive side effects with 9-tetrahydrocannabinoltreatment. This has led again to a search for methods to improve cannabinoid therapy. For this reason researchhas focused on the ~150 terpene compounds found in Cannabis which impart flavor and aroma to the plant.Limited evidence suggests that terpenes produce pain relief on their own and they have also been proposed tomodulate and potentially improve the effects of cannabinoids like THC termed the entourage effect hypothesis.However the quality of evidence on terpene efficacy is in general poor limited by poorly-defined and complexextracts and few mechanistic studies. We thus performed a preliminary study on the Cannabis terpenes -humulene -pinene geraniol and linalool. We found that all 4 terpenes produced anti-nociception in amouse model of chemotherapy-induced peripheral neuropathy (CIPN) comparable or better thanmorphine. At the same time geraniol and linalool produced no reward or aversion suggesting no addictiveor aversive liability. Seeking mechanistic insight we found that all 4 terpenes produced tail flick anti-nociception by a cannabinoid receptor type 1 (CB1) mechanism and further synergized with thecannabinoid WIN55212 providing evidence for the entourage effect hypothesis. We further identified CB2Adenosine A2a and anti-inflammatory activity as potential mechanisms of action. In this proposal we willextend these studies to evaluate therapeutic potential and mechanisms of action of these terpenes in neuropathicpain providing potential support to the use of these ligands as improved non-opioid pain therapeutics. In Aim 1we will fully test the terpenes in a mouse model of CIPN including dose/response alternate neuropathy modelsside effects like tolerance and reward/aversion synergy with other analgesics such as opioids and cannabinoidsand terpene impact on side effects of these other analgesics (especially opioid reward). In Aim 2 we will identifymolecular mechanisms for terpene action in CIPN focusing on 1) CB1/2 2) A2a and 3) anti-inflammatoryactivity. We will use selective antagonists and CRISPR gene editing identify sites of action (e.g. brain spinalcord periphery) measure tissue response to terpene (e.g. cytokine production) and use in vitro models toconfirm these mechanisms. Together these studies will provide a rigorous evaluation of the potential use ofterpenes as efficacious and low side-effect therapeutics for neuropathic pain.