Modulation of pain hypersensitivity by terpenes via endocannabinoid release in descending circuits - Project Abstract Twenty percent of US adults suffer from chronic pain, a condition characterized by reduced mental and physical well-being, and despite current treatments over half of patients experience undertreated pain symptoms. Although the most efficacious medications for pain are opioids, they possess serious side effects and long-term consequences, highlighting the importance of identifying novel therapeutics for treating pain. There is established clinical and preclinical evidence that cannabis (a plant containing over 550 chemical compounds including terpenes) possesses analgesic/anti-allodynic effects, at least partially explained by cannabis’s action on cannabinoid 1 (CB1) receptors. Cannabis strains with high terpene (odor-causing molecules of the cannabis plant) concentrations are preferred among patients who use cannabis, and preclinical work on rodents (demonstrated by the applicant) has shown terpenes can produce antiallodynic effects in pain models, which was blocked by CB1 receptor antagonists despite not directly binding to these receptors. In order to advance the understanding of how terpenes interplay with the endocannabinoid system to relieve pain, the goal of this proposed research is to elucidate how terpenes may alter eCB levels using a sophisticated and novel modified eGFP CB1 receptor sensor. The ventrolateral periaqueductal gray (vlPAG), a region involved in the descending modulation of pain, has a dense population of CB1 receptors and stimulating this area induces analgesia. This sensor paired with fiber photometry will be used to measure endocannabinoid release in the vlPAG in vivo in mouse models of chronic pain. The Cahill laboratory uses a Chronic Constriction Injury (CCI) model of neuropathic chronic pain in mice that captures the acute hypersensitivity and negative affect associated with chronic pain in humans. By naturally increasing endocannabinoids via inhibitors of their degradation (FAAH/MAGL inhibitors), Aim 1 will determine if myrcene can augment changes in hyperalgesia and negative-affect like behaviors in CCI mice, partially attenuated by knockdown or antagonism of vlPAG CB1 receptors. Aim 2 will address mechanism of action by directly measuring endocannabinoid release using a genetically modified eGFP CB1 receptor sensor in awake, freely-moving animals. This will be achieved by measuring endocannabinoid release before and after terpene administration in the vlPAG. Such findings would identify non-intoxicating, FDA-approved compounds that rapidly modulate endocannabinoid levels as a potential therapeutic strategy. UCLA contains supportive and collaborative atmosphere with personnel specializing in photometry, in-house virus packaging, and resources from an established chronic pain laboratory. This productive an integrative environment will support this trainee plan for a scientist with a disadvantaged background toward her goals of conducting her own research laboratory at an R1 institution.
