Sex Differences in Opioid Analgesia

阿片类镇痛的性别差异

• 批准号: 6531444
• 负责人: ANNE Z MURPHY
• 金额: $ 29.38万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6531444
• 关键词: analgesia; analgesics; brain imaging /visualization /scanning; brain morphology; chronic pain; gender difference; immunocytochemistry; laboratory rat; morphine; neuropharmacology; opiate alkaloid; periaqueductal gray matter; pons; receptor expression; steroid hormone; steroid hormone receptor

DESCRIPTION (provided by applicant): Chronic pain afflicts millions of people each year. Opioid-based narcotics are the most prevalent therapeutic treatment for chronic pain management, with morphine being the most commonly prescribed. There are now well-established sex differences in the ability of morphine to alleviate pain; in animals models of acute pain, the effective dose of morphine is approximately 5-lOx greater for females in comparison to males. Similar results have been reported in humans. To date, the underlying mechanisms mediating sex differences in opiate sensitivity are not known. The midbrain periaqueductal gray (PAG) and its descending projections to the nucleus raphe magnus (NRM) are an essential endogenous neural circuit for opioid-based analgesia. Our major hypothesis is that the opiate-sensitive intrinsic and extrinsic circuitry of the FAG is sexually dimorphic and is the major determinant of sex-based differences in opioid analgesia. Previous studies examining the dimorphic effect of opioid administration utilized acute assays of nociception. Studies proposed in Aim 1 will characterize the sexually dimorphic effect of central morphine administration using a model of chronic inflammatory pain. Our preliminary data indicate that the PAG-NRM pathway is sexually dimorphic. Studies proposed in Aim 2 will use neural tract tracing techniques to delineate the anatomical organization of the PAG-NRM-spinal cord circuit in males and females. Aim 3 will examine the functional organization of this circuit in a model of prolonged inflammatory pain. The PAG is enriched in opioid receptors. Studies proposed in Aim 4 will characterize both the distribution and expression pattern of the opioid receptors. The influence of chronic inflammatory pain and gonadal steroid manipulations will also be examined. In summary, these studies will establish that the intrinsic and extrinsic circuitry of the PAG is sexually dimorphic and provide the neural substrate for sex based differences in opioid analgesia.

描述（由申请人提供）：慢性疼痛每年困扰着数百万人。以阿片类药物为基础的麻醉剂是治疗慢性疼痛最普遍的治疗方法，其中吗啡是最常用的处方药。现在，吗啡缓解疼痛的能力存在明显的性别差异。在急性疼痛动物模型中，雌性吗啡的有效剂量比雄性大约高 5-10 倍。在人类身上也有类似的结果。迄今为止，调节阿片敏感性性别差异的潜在机制尚不清楚。中脑导水管周围灰质（PAG）及其到中缝大核（NRM）的下降投影是阿片类镇痛的重要内源性神经回路。我们的主要假设是，FAG 对阿片类药物敏感的内在和外在回路具有性别二态性，并且是阿片类镇痛性别差异的主要决定因素。先前的研究利用急性伤害感受测定阿片类药物的二态性效应。目标 1 中提出的研究将使用慢性炎症疼痛模型来表征中枢吗啡给药的性别二态效应。我们的初步数据表明 PAG-NRM 途径是性别二态性的。目标 2 中提出的研究将使用神经束追踪技术来描绘男性和女性 PAG-NRM-脊髓回路的解剖结构。目标 3 将在长期炎性疼痛模型中检查该回路的功能组织。 PAG 富含阿片受体。目标 4 中提出的研究将描述阿片受体的分布和表达模式。还将检查慢性炎症疼痛和性腺类固醇操作的影响。总之，这些研究将确定 PAG 的内在和外在回路具有性别二态性，并为阿片类镇痛中基于性别的差异提供神经基础。