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δ（DOR）和μ（莫尔）亚型广泛分布于中枢和外周神经系统。内源性阿片肽和许多外源性阿片激动剂（包括吗啡）都靶向这些受体。尽管多年的研究，仍然有许多未回答的问题，关于DOR和莫尔对阿片激动剂影响的复杂行为的不同贡献，包括疼痛控制，成瘾和奖励。在某种程度上，缺乏进展反映了可用于研究不同CNS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δ阿片受体（DOReGFP）报告小鼠，从而对受作用于DOR的激动剂影响的回路进行了完整的重新评估。与流行的观点相反，我们发现DOR和莫尔在背根神经节（DRG）“疼痛”传递神经元（伤害感受器）的非重叠子集中表达，并调节不同的疼痛模式。DOR在有髓鞘感觉神经元和非肽能无髓鞘伤害感受器的子集中表达，并调节机械性疼痛和在损伤情况下产生的机械性超敏反应。莫尔在肽能伤害感受器中占主导地位，肽能伤害感受器表达辣椒素和热响应通道TRPV 1，并调节热痛。本提案是在这些意见的基础上提出的。特定目标1的研究将使用神经解剖学方法评估正常动物和组织或神经损伤环境中脊髓和脑中DOR和莫尔分离的程度。具体目标2使用行为学、药理学和遗传学方法的组合来确定DRG和脊髓神经元表达DOR和莫尔对伤害性感受处理和阿片类化合物的抗伤害性感受作用的差异贡献。最后，具体目标3将药理学分析扩展到DOR和莫尔激动剂作用对脊髓上靶点的差异贡献。总之，这些研究将不仅提供新的信息，组织内源性阿片受体系统，但也将评估在何种程度上不同的形式的疼痛可以控制阿片激动剂，选择性靶向这些受体，在外周和中枢神经系统。从这些研究中获得的信息将为开发具有更好副作用的止痛药物做出重要贡献。

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.