UCLA

Leveraging analgesic constituents of the cannabis plant, which has been used for centuries, has considerable potential in addressing the unmet need for effective analgesics. Understanding the effects of terpene isolates, such as myrcene, in pain response will advance this goal. Chronic pain is a condition that impairs people’s quality of life and affects approximately 1/5th of the population. Myrcene is a cannabis terpene that has demonstrated analgesic potential but a gap in the literature exists on pharmacological and behavioral experiments to characterize myrcene’s mechanism of action and understanding how its properties relate to the endocannabinoid (eCB) system. My dissertation work characterized the therapeutic potential and pharmacology of myrcene, using four distinct experimental approaches. I used behavioral pharmacology in a mouse model of neuropathic pain, TRUPATH binding assays with HEK293 cells, molecular structural elucidation with Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS), and in vivo fiber photometry. I aimed to support or refute the following two hypotheses: 1) Myrcene produces anti-allodynic effects via engagement of the endocannabinoid system. 2) Myrcene modulates vlPAG neuronal activity in response to a painful aversive stimulus but not a non-painful stimulus. Secondary hypotheses: Myrcene anti-allodynic effects will be prevented by blocking synthesis of endocannabinoid production and will cause endocannabinoids to increase in the vlPAG at time points consistent with peak anti-allodynic effects. My work confirmed that myrcene produces anti-allodynic effects to attenuate mechanical hypersensitivity in male mice with a chronic constriction injury (CCI) and demonstrate a dose-dependent shift to the left in female CCI mice without modulating antinociception in either sex in sham control groups. I established myrcene requires the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) to produce these effects in both male and female CCI mice. I also demonstrated that myrcene does not directly activate CB1 receptors via G1alpha using a TRUPATH assay in vitro. However, myrcene increased 2-AG levels as quantified by LC-MS/MS at times consistent with peak anti-allodynic effects. Although capable of increasing eCBs, myrcene did not modulate neuronal activity in the same way as a CB1 agonist in the ventrolateral periaqueductal gray (vlPAG), an integral area in the descending modulation of pain. These findings provide clarification of how myrcene alleviates neuropathic pain as well as specific circuitry that appear not to be involved in this modulation of sensory pain hypersensitivity. Overall, this work supports that myrcene is engaging the eCB system to produce anti-allodynic effects.