Gender differences in peripheral cannabinoid mediated analgesia

描述(申请人提供)：与男性相比，口腔面部肌肉疼痛在女性中更为普遍和严重。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相关的机制还不完全清楚，目前对口面部肌肉疼痛的治疗在很大程度上是不够的。由于与阿片类药物治疗有关的中心相关副作用，大麻类药物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药物。外周注射大麻素在炎症条件下产生性别依赖性的镇痛反应，这可能是由于三叉神经节(TG)中CB1表达的差异。炎症细胞因子已被证明调节阿片和大麻素受体的表达。本研究旨在探讨炎性细胞因子是否比女性更能诱导男性TG中CB1的上调，以及雌二醇是否参与了细胞因子诱导CB1表达的性别差异。实时RT-PCR和免疫印迹实验将测试(1)炎性细胞因子是否通过在TG原代培养中应用细胞因子而诱导雄性比女性更大程度地上调CB1的表达，以及(2)炎性细胞因子是否通过将细胞因子直接注入完整动物的咬肌而导致雄性比女性更大程度地上调CB1的表达。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以及外周大麻素受体介导的镇痛的性别差异。 公共卫生相关性：与颞下颌关节紊乱病相关的口面部肌肉疼痛影响大约10%-12%的人口，女性的患病率高于男性。由于病因学、病理生理学和与性别相关的机制还不完全清楚，目前对这些疼痛状况的治疗仍然不足。根据NIDCR和FOA：PA-10-107的任务，本研究建议研究炎性细胞因子是否诱导TG中性别依赖性CB1的表达，以及雌二醇是否调节这种诱导。了解在外周大麻素介导的镇痛中潜在的性别差异的机制将有助于开发基于性别和基于机制的治疗措施来治疗炎症性口面部肌肉疼痛。这项提议将作为一个平台，让我可以发展成为一名临床医生/科学家。

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.