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: 8060787
• 负责人: Katelyn Yueyi Niu
• 金额: $ 3.16万
• 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 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060787
• 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; 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; 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，女性的口面部肌肉疼痛更为普遍且严重。性别差异在个体对治疗的反应中也发挥着重要作用。然而，由于病因学、病理生理学和性相关机制尚未完全了解，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相关的主要副作用，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品或辅助药物。外周施用大麻素在炎症条件下会产生性别依赖性镇痛反应，这可能是由于三叉神经节 (TG) 中 CB1 表达的差异所致。炎症细胞因子已被证明可以调节阿片类药物和大麻素受体的表达。本研究旨在调查炎症细胞因子是否会诱导男性 TG 中 CB1 的上调程度高于女性，以及雌二醇是否与细胞因子诱导 CB1 的性别差异有关。实时 RT-PCR 和蛋白质印迹实验将测试 (1) 通过在 TG 原代培养物中应用细胞因子，炎症细胞因子是否会诱导雄性比雌性更大的 CB1 表达上调；(2) 通过直接将细胞因子注射到完整动物的咬肌中，炎症细胞因子是否会诱导雄性比雌性更大的 CB1 表达上调。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中的性别差异的潜在机制。 公共卫生相关性：与颞下颌疾病相关的口面部肌肉疼痛影响大约 10-12% 的人口，其中女性患病率高于男性。由于病因学、病理生理学和性相关机制尚未完全了解，目前对这些疼痛的治疗仍然不足。根据 NIDCR 和 FOA: PA-10-107 的使命，本研究拟调查炎症细胞因子是否诱导 TG 中性别依赖性 CB1 表达以及雌二醇是否调节这种诱导。了解外周大麻素介导的镇痛中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干预措施，用于治疗炎症性口面部肌肉疼痛。该提案将作为我发展成为临床医生/科学家的平台。