Multiple Opioid Receptors and the Control of Pain

描述（由申请人提供）：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周围神经系统。这些受体是内源性阿片肽和外源性阿片激动剂（包括吗啡）的靶点。尽管经过多年的研究，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，仍有许多未解之谜。在某种程度上，缺乏进展反映了可用于研究不同中枢神经系统回路中受体的表达，相互作用和功能的工具。为此，我们开发了一种delta阿片受体（DOReGFP）报告小鼠，对作用于DOR的激动剂影响的回路进行了全面的重新评估。与主流观点相反，我们发现DOR和MOR在背根神经节（DRG）“疼痛”传递神经元（伤害感受器）的非重叠亚群中表达，并调节不同的疼痛模式。DOR在有髓鞘感觉神经元和非多肽性无髓鞘伤害感受器中表达，并调节损伤时产生的机械性疼痛和机械性超敏反应。MOR在肽能伤害感受器中占主导地位，该感受器表达辣椒素和热反应通道TRPV1，并调节热痛。本建议是根据这些意见提出的。Specific Aim 1中的研究将使用神经解剖学方法来评估DOR和MOR分离在脊髓和大脑、正常动物和组织或神经损伤情况下发生的程度。特异性目的2结合行为学、药理学和遗传学方法来确定DRG和DOR和MOR的脊髓神经元表达对伤害性加工和阿片类化合物的抗伤害性作用的差异贡献。最后，Specific Aim 3将把药理学分析扩展到DOR和MOR激动剂作用在脊柱上靶点的差异贡献。综上所述，这些研究不仅将为内源性阿片受体系统的组织提供新的信息，而且还将评估在何种程度上，阿片受体激动剂可以选择性地靶向这些受体，在外围和中枢神经系统中控制不同形式的疼痛。从这些研究中得到的信息将是开发具有更好副作用的止痛药的重要贡献者。

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.