Peripheral Opioid Receptors and Analgesia

描述(申请人提供)：阿片类化合物是有效的中枢止痛剂，但全身给药通常伴随着不良反应，如镇静、胃肠紊乱和呼吸抑制。此外，长期使用不可避免地会导致耐受性、退缩和成瘾。这一建议涉及外周阿片受体的功能，以及它们的激活如何有助于中枢神经系统外的内源性阿片止痛系统。我们已经在正常的角膜和皮肤上表明，直接外周应用吗啡在改变急性伤害性反应方面并不有效。然而，在炎症组织中，外周吗啡以浓度依赖和纳洛酮可逆的方式逆转角膜的行为痛敏，并降低已识别的皮肤伤害性感受器的兴奋性。我们现在试图确定这种内源性阿片系统在什么条件下是有效的，以及在损伤或炎症后，什么机制有助于增强外周阿片受体的可用性。电生理学技术将被用来确定(1)哪种阿片受体类型介导了吗啡对支配炎症躯体组织的已识别的传入神经元的抑制作用，以及(2)在神经病理性疼痛的实验模型中，感觉神经元是否对吗啡产生敏感性。定量免疫组织化学将确定(3)炎症和神经病变条件下感觉神经元胞体和外周突起阿片受体表达的时间进程，以及(4)炎症后感觉神经元外周突起膜上是否可检测到阿片受体数量的增加。更好地了解内源性阿片系统是如何受到调节的，将为开发替代传统全身阿片类药物以缓解疼痛的治疗方案提供有价值的见解。

DESCRIPTION (provided by applicant): Opiate compounds are potent and effective centrally acting analgesic agents, but systemic administration is usually accompanied by undesirable effects such as sedation, gastrointestinal disturbance, and respiratory depression. In addition, tolerance, withdrawal, and addiction inevitably result from prolonged use. This proposal concerns the function of opioid receptors in the periphery, and how their activation contributes to an endogenous opioid analgesia system operating outside the central nervous system. We have shown in normal cornea and skin that direct peripheral application of morphine is not effective in altering acute nociceptive responses. However, in inflamed tissue, peripheral morphine reverses behavioral hyperalgesia in cornea and reduces excitability of identified cutaneous nociceptors in a concentration-dependent and naloxone reversible fashion. We now seek to determine under what conditions this endogenous opioid system is effective, and what mechanisms contribute to enhanced availability of peripheral opioid receptors after injury or inflammation. Electrophysiological techniques will be used to determine (1) which opioid receptor types mediate the inhibitory effects of morphine on identified afferent neurons innervating inflamed somatic tissue, and (2) if sensory neurons develop a sensitivity to morphine in an experimental model of neuropathic pain. Quantitative immunohistochemistry will determine (3) the time course of changes in expression of opioid receptors in the somata and peripheral processes of sensory neurons under inflammatory and neuropathic conditions, and (4) if increased numbers of opioid receptors are detectable on the membranes of peripheral processes of sensory neurons following inflammation. Better understanding of how endogenous opioid systems are regulated would provide valuable insights into potential development of therapeutic alternatives to traditional systemic delivery of opiates for the relief of pain.