Gender differences in peripheral cannabinoid mediated analgesia

描述（由申请人提供）：与男性相比，女性的口面部肌肉疼痛更为普遍和严重。性别差异在个体对治疗的反应中也起着重要作用。然而，由于病因、病理生理学和与性别有关的机制尚不完全清楚，目前对口面部肌肉疼痛的治疗在很大程度上是不充分的。由于与阿片类药物治疗相关的中枢相关副作用，大麻素的外围使用已成为阿片类药物治疗的有吸引力的替代品或辅助物。外周给药大麻素在炎症条件下产生性别依赖性镇痛反应，可能是由于三叉神经节（TG）中CB1表达的差异。炎性细胞因子已被证明可以调节阿片和大麻素受体的表达。本研究拟探讨炎性细胞因子诱导TG中CB1的上调是否在男性高于女性，以及雌二醇是否参与了细胞因子诱导CB1的性别差异。Real-time RT-PCR和western blot实验将测试(1)通过在TG原代培养中应用细胞因子，炎症因子是否诱导雄性CB1表达的上调幅度大于雌性；(2)通过在完整动物咬肌中直接注射细胞因子，炎症因子是否诱导雄性CB1表达的上调幅度大于雌性。这项研究将有助于更好地理解炎症条件下CB1表达调节的性别差异机制以及外周大麻素受体介导的镇痛的性别差异。

DESCRIPTION (provided by applicant): Orofacial muscle pain is much more prevalent and severe in women compared to men. Sex differences also play an important role in individuals' responses to treatment. However, with etiology, pathophysiology and sex-related mechanisms not fully understood, current treatments for orofacial muscle pain conditions are largely inadequate. Peripheral uses of cannabinoids have emerged as attractive alternatives or adjuncts to treatment with opioids, due to the centrally related side effects associated with opioids treatments. Peripheral administration of cannabinoids produces sex-dependent analgesic responses under inflammatory conditions and is likely due to the differential CB1 expression in trigeminal ganglia (TG). Inflammatory cytokines have been shown to modulate both opioid and cannabinoid receptor expression. This study proposes to investigate whether inflammatory cytokines induce greater up-regulation of CB1 in TG in males than females, and whether estradiol is involved in the sex differences in the induction of CB1 by cytokines. Real-time RT-PCR and western blot experiments will test (1) whether inflammatory cytokines induce a greater up-regulation of CB1 expression in males than females by applying cytokines in TG primary cultures and (2) whether inflammatory cytokines induce a greater up-regulation of CB1 expression in males than females by directly injecting cytokines into the masseter muscle in intact animals. This study will lead to better understanding of the mechanisms underlying sex differences in the regulation of CB1 expression under inflammatory conditions and sex differences in peripheral cannabinoid receptor-mediated analgesia. PUBLIC HEALTH RELEVANCE: Orofacial muscle pain related to temporomandibular disorders affects approximately 10-12% of the population, with a higher prevalence in women than in men. With etiology, pathophysiology and sex-related mechanisms not fully understood, current treatments for these pain conditions are still inadequate. In accordance with the missions of the NIDCR and the FOA: PA-10-107 this study proposes to investigate whether inflammatory cytokines induce sex-dependent CB1 expression in TG and whether estradiol modulates this induction. Understanding the mechanisms underlying sex differences in peripheral cannabinoid-mediated analgesia will enable the development of sex-based and mechanism-based therapeutic interventions for the treatment of inflammatory orofacial muscle pain. This proposal will serve as a platform on which I can develop into a clinician/scientist.