Role of pre- and postsynaptic mu opioid receptors in antinociception and tolerance

 描述(申请人提供)：吗啡和其他阿片类药物是非常有效的治疗疼痛的药物，但其抗伤害作用因持续服用而受到不良副作用的限制，包括阿片类药物引起的痛觉过敏、耐受和依赖。目前，美国每年花费超过86亿美元用于与使用和滥用处方阿片类药物相关的健康、工作和法律问题。这些副作用和阿片类药物诱导的突触可塑性背后的机制一直很难阐明，主要是因为我们对内源性疼痛控制系统是如何被大脑激活和调节的有一个初步的了解。中脑导水管周围灰质区(PAG)GABA能终末上的突触前阿片受体(MOPrs)激活下行的抗伤害性感觉通路至脊髓。然而，MOPrs也在PAG神经元的胞体和树突中大量表达，这些突触后受体的作用尚不清楚。我们推测，突触后MOPrs负责阿片类药物耐受的适应。拟议的研究将通过体内注射siRNA结构选择性地击倒突触后MOPrs来验证这一假说。具体目标#1将测试敲除突触后MOPrs是否减弱吗啡诱导的抗伤害性感觉。具体目标#2将确定是否可以将接受siRNA预处理的吗啡耐受大鼠的抗伤害性感觉恢复到正常水平。我们期望这些研究将证实，突触后MOPrs调节下行痛觉调制回路的增益，是长期给药不会引起痛觉过敏、耐受和依赖等不良副作用的止痛治疗的合适靶点。这些研究还将为R01的应用奠定基础，该应用侧重于了解突触后MOPr调节内源性下行痛觉调制回路的分子机制。

 DESCRIPTION (provided by applicant): Morphine and other opioids are extremely effective therapeutic drugs for treating pain, but their antinociceptive effects are limited by detrimental side effects with continued administration, including opioid-induced hyperalgesia, tolerance and dependence. Currently, over $8.6 billion a year are spent in the U.S. for health, work, and legal issues associated with the use and abuse of prescription opioids. The mechanisms underlying these side effects and opioid-induced synaptic plasticity have been difficult to elucidate, primarily because we have a rudimentary understanding of how endogenous pain control systems are activated and regulated by the brain. It is known that presynaptic mu opioid receptors (MOPrs) on GABAergic terminals in the periaqueductal gray area (PAG) activate the descending antinociceptive pathway to the spinal cord. However, MOPrs are also abundantly expressed in the soma and dendrites of PAG neurons and the role of these postsynaptic receptors is not known. We hypothesize that the postsynaptic MOPrs are responsible for the adaptations in opioid tolerance. The proposed studies will test this hypothesis with selective knock-down of the postsynaptic MOPrs using in vivo administration of siRNA constructs. Specific Aim #1 will test whether knock-down of the postsynaptic MOPrs attenuates morphine-induced antinociception. Specific Aim #2 will determine if antinociception can be rescued to normal levels in morphine tolerant rats that have received the siRNA pretreatment. We expect that these studies will confirm that postsynaptic MOPrs regulate the gain of the descending pain modulatory circuit and are appropriate targets for analgesic therapies that do not induce detrimental side-effects such as hyperalgesia, tolerance and dependence with long-term administration. The studies will also lay the groundwork for an R01 application focused on understanding the molecular mechanisms of postsynaptic MOPr regulation of the endogenous descending pain modulatory circuit.