Sex Differences in Opioid Analgesia

描述（由申请人提供）：慢性疼痛每年折磨数百万人。基于阿片类药物的麻醉剂是用于慢性疼痛管理的最普遍的治疗性治疗，其中吗啡是最常用的处方。在吗啡缓解疼痛的能力方面，现在已经确定了性别差异;在急性疼痛的动物模型中，与雄性相比，雌性的吗啡有效剂量大约高5- 10倍。在人类中也有类似的结果。迄今为止，介导阿片类药物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）及其向中缝大核（NRM）的下行投射是阿片类镇痛的重要内源性神经回路。我们的主要假设是，阿片类药物敏感的内在和外在电路的FAG是性别二态性，是阿片类镇痛的性别差异的主要决定因素。以前的研究检查阿片类药物的二态效应利用急性伤害性试验。目的1中提出的研究将使用慢性炎性疼痛模型描述中枢吗啡给药的性二态效应。我们的初步数据表明，PAG-NRM途径是性二态的。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的PAG-NRM-脊髓回路的解剖组织。目的3将在长期炎症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。慢性炎性疼痛和性腺类固醇激素的影响也将进行检查。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，并为阿片类镇痛的性别差异提供神经基质。

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.