Gender differences in peripheral cannabinoid mediated analgesia

外周大麻素介导的镇痛的性别差异

• 批准号: 8460770
• 负责人: Katelyn Yueyi Niu
• 金额: $ 4.37万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460770
• 关键词: Absence of pain sensation; Adverse effects; Affect; Afferent Neurons; Agonist; Analgesics; Animals; Anti-Inflammatory Agents; Attenuated; Behavioral; Biological Models; Cannabinoids; Clinical Research; Data; Development; Estradiol; Estrogen Receptors; Estrogen Replacements; Estrogens; Etiology; Female; Functional disorder; Goals; High Prevalence; Hyperalgesia; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Interleukin-6; Lead; Literature; Masseter Muscle; Mechanics; Mediating; Mediator of activation protein; Messenger RNA; Mission; Modeling; Muscle; Myalgia; National Institute of Dental and Craniofacial Research; Opioid; Opioid Receptor; Outcome Study; Pain; Peripheral; Pharmaceutical Preparations; Play; Population; Preparation; Prevalence; Proteins; Rattus; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Role; Scientist; Severities; Sex Characteristics; Sexual Development; Structure of trigeminal ganglion; System; TNF gene; Temporomandibular Joint Disorders; Testing; Therapeutic; Therapeutic Intervention; Time; Trigeminal System; Up-Regulation; Western Blotting; Woman; base; cannabinoid receptor; chronic pain; compliance behavior; cytokine; desensitization; male; men; novel; orofacial; pre-clinical; public health relevance; receptor; receptor expression; research study; response; sex

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.

描述（由申请人提供）：与男性相比，女性的口面肌肉疼痛更为普遍和严重。性别差异在个人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尚未完全理解，目前对口面肌肉疼痛状况的治疗基本上是不足的。由于与阿片类药物相关的副作用，大麻素的外围用途已成为阿片类药物治疗的有吸引力的替代方案或辅助方法。大麻素的外围给药在炎症条件下会产生性依赖性镇痛反应，并且可能是由于三叉神经节（TG）中的CB1表达差异所致。炎性细胞因子已显示可调节阿片类药物和大麻素受体表达。这项研究建议研究炎性细胞因子是否比女性诱导TG中CB1的上调更大，以及雌二醇是否参与细胞因子诱导CB1的性别差异。实时RT-PCR和Western印迹实验将测试（1）炎性细胞因子是否通过在TG原发性培养物中应用细胞因子来诱导男性中CB1表达的上调是否更大，并且（2）炎症细胞因子是否会通过注入cytoteter insent cytokete insent cytokete insent cytokeins cytoke insents cytoke insent cytoke inspote cytokine cytokine cytokine note cytokine cytokine cytokine cytokine cytokine cye的表达是否更大。这项研究将更好地理解在炎症条件下CB1表达的性别差异和周围大麻素受体介导的镇痛的性别差异的机制。 公共卫生相关性：与颞下颌疾病有关的口面肌肉疼痛影响大约10-12％的人口，女性患病率高于男性。鉴于病因，病理生理学和与性别相关的机制尚未完全理解，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，本研究提议研究炎性细胞因子是否在TG中诱导性别依赖性CB1表达以及雌二醇是否会调节这种诱导。了解周围大麻素介导的镇痛的性别差异的基础机制将使基于性别和机制的治疗干预措施的发展用于治疗炎症性类似肌肉疼痛。该建议将作为我可以在临床医生/科学家发展的平台。