Peripheral Opioid Receptors and Analgesia

外周阿片受体和镇痛

• 批准号: 7074555
• 负责人: Christopher Nick Honda
• 金额: $ 25.38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7074555
• 关键词: Freund' s adjuvant; afferent nerve; analgesia; electrophysiology; endogenous opioid; immunocytochemistry; inflammation; injury; laboratory rat; morphine; neuropathology; opioid receptor; pain; peripheral nervous system; receptor expression

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.

描述（由申请人提供）：阿片类化合物是强效和有效的中枢作用镇痛剂，但全身给药通常伴有不良反应，如镇静、胃肠道紊乱和呼吸抑制。此外，耐受性、戒断和成瘾不可避免地是长期使用的结果。这一提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镇痛系统。我们在正常角膜和皮肤中发现，直接外周应用吗啡对改变急性伤害性反应无效。然而，在炎症组织中，外周吗啡逆转角膜中的行为痛觉过敏，并以浓度依赖性和纳洛酮可逆的方式降低识别的皮肤伤害感受器的兴奋性。我们现在试图确定在什么条件下这种内源性阿片系统是有效的，以及什么机制有助于增强损伤或炎症后外周阿片受体的可用性。电生理学技术将用于确定（1）哪些阿片受体类型介导吗啡对支配发炎躯体组织的已鉴定传入神经元的抑制作用，以及（2）在神经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）在炎症和神经病理条件下感觉神经元的胞体和外周过程中阿片受体表达变化的时间过程，和（4）在炎症后感觉神经元的外周过程的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调节的，将为开发替代传统阿片类药物全身给药缓解疼痛的治疗方法提供有价值的见解。