Sex Differences in Opioid Analgesia

描述(申请人提供)：每年有数百万人遭受慢性疼痛的折磨。阿片类麻醉剂是慢性疼痛治疗中最普遍的治疗方法，吗啡是最常用的处方。现在，在吗啡缓解疼痛的能力方面存在着公认的性别差异；在急性疼痛的动物模型中，女性的吗啡有效剂量大约比男性高5倍。类似的结果在人类身上也有报道。到目前为止，调节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药物镇痛的重要内源性神经回路。我们的主要假设是，烟雾剂敏感的内在和外在回路是性二态的，是阿片类药物镇痛作用性别差异的主要决定因素。以前研究阿片类药物给药的二态效应时使用的是急性伤害性试验。在目标1中提出的研究将使用慢性炎症性疼痛的模型来表征中枢吗啡给药的性二态效应。我们的初步数据表明，PAG-NRM通路是性二态的。在Aim 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-脊髓回路的解剖组织。目的3将在一个长期炎症性疼痛的模型中检查这个回路的功能组织。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。慢性炎症性疼痛和性腺类固醇操作的影响也将被检查。综上所述，这些研究将确定PAG的内、外回路是性二态的，并为阿片类药物镇痛中基于性别的差异提供神经底物。

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.