Multiple Opioid Receptors and the Control of Pain

描述(申请人提供)：G蛋白偶联阿片受体的Delta(DOR)和MU(MOR)亚型广泛分布于中枢和外周神经系统。这些受体既是内源性阿片肽的靶标，也是包括吗啡在内的一系列外源性阿片激动剂的靶标。尽管多年来的研究，关于DOR和MOR对阿片类激动剂影响的复杂行为(包括疼痛控制、成瘾和奖励)的不同贡献，仍有许多悬而未决的问题。在某种程度上，缺乏进展反映了可用于研究受体在不同中枢神经系统回路中的表达、相互作用和功能的工具。为此，我们开发了一种增量阿片受体(DOReGFP)报告小鼠，它导致了对作用于DOR的激动剂影响的回路的完全重新评估。与流行的观点相反，我们发现DOR和MOR在背根节(DRG)“痛”传递神经元(伤害性感受器)的不重叠亚群中表达，并调节不同的疼痛方式。DOR在有髓感觉神经元和非肽能无髓伤害性感受器中表达，调节机械性疼痛和损伤时产生的机械超敏反应。MOR在表达辣椒素和热反应通道TRPV1的多肽能伤害性感受器中占主导地位，并调节热痛。本提案建立在这些观察的基础上。具体目标1的研究将使用神经解剖学方法来评估在正常动物和组织或神经损伤的背景下，脊髓和大脑中DOR和MOR分离的程度。特定目的2结合行为学、药理学和遗传学的方法，确定DOR和MOR的DRG和脊髓神经元表达在伤害性加工和阿片类化合物的抗伤害性感受效应中的不同贡献。最后，具体目标3将扩展药理学分析，以确定DOR和MOR激动剂作用于脊髓上靶点的不同贡献。综上所述，这些研究不仅将提供关于内源性阿片受体系统的组织的新信息，而且还将评估在外周和中枢神经系统中，选择性靶向这些受体的阿片激动剂可以在多大程度上控制不同形式的疼痛。从这些研究中获得的信息将是开发副作用更好的止痛药的重要贡献。

DESCRIPTION (provided by applicant): The delta (DOR) and mu (MOR) subtypes of G protein-coupled opioid receptors are widely distributed in the central and peripheral nervous system. These receptors are targeted both by endogenous opioid peptides and by a host of exogenous opiate agonists, including morphine. Despite years of research, there are still numerous unanswered questions concerning the differential contribution of the DOR and MOR to the complex behaviors influenced by opioid agonists, including pain control, addiction and reward. In part, the lack of progress reflects the tools that are available to study the expression, interaction and function of the receptors in different CNS circuits. To this end, we have developed a delta opioid receptor (DOReGFP) reporter mouse that led to a complete reappraisal of the circuits that are influenced by agonists that act at the DOR. Contrary to the prevailing view, we find that the DOR and the MOR are expressed in non-overlapping subsets of dorsal root ganglia (DRG) "pain" transmission neurons (nociceptors) and regulate distinct pain modalities. The DOR is expressed in myelinated sensory neurons and in a subset of the non-peptidergic unmyelinated nociceptors and regulates mechanical pain and the mechanical hypersensitivity produced in the setting of injury. The MOR predominates in the peptidergic nociceptors, which express the capsaicin and heat responsive channel, TRPV1, and regulates heat pain. The present proposal builds upon these observations. Studies in Specific Aim 1 will use neuroanatomical methods to assess the extent to which segregation of the DOR and MOR also occurs in the spinal cord and brain, in the normal animal and in the setting of tissue or nerve injury. Specific Aim 2 uses a combination of behavioral, pharmacological and genetic methods to determine the differential contribution of the DRG and spinal cord neuron expression of the DOR and MOR to nociceptive processing and to the antinociceptive effects of opioid compounds. Finally, Specific Aim 3 will extend the pharmacological analysis to the differential contribution of DOR and MOR agonist action at supraspinal targets. Taken together these studies will not only provide new information as to the organization of endogenous opioid receptor systems, but will also assess the extent to which different modalities of pain can be controlled by opioid agonists that selectively target these receptors, in the peripheral and central nervous systems. Information derived from these studies will be an important contributor to the development of pain-relieving drugs with better side effect profiles.