OFQ MODULATION OF OPIOID EFFECTS

描述(申请人摘要)：阿片类药物是一种有效的止痛药。 不幸的是，长期使用这些药物往往会导致上瘾和耐受， 严重限制其临床应用的责任。更改在 细胞和阿片受体水平已被证明是不充分的解释 宽容和依赖。一个令人兴奋的替代假设是 “抗阿片”系统、神经递质或神经肽 对抗阿片受体激活效应，促进耐受 和依赖性以及阿片类药物镇痛效力的变化 一些病理性疼痛状态。我们最近展示了孤儿症 FQ(OFQ，也被称为伤害素)是一种内源性的 阿片样G蛋白偶联受体LC132及其逆转 吗啡诱导的镇痛、低温和Straub尾巴反应。这些抗阿片类药物 OFQ/N的作用及其与内源性的密切进化亲缘关系 阿片肽提示OFQ/LC132神经递质系统可能发挥作用 在阿片类药物机制的动态平衡中发挥重要作用。我们提出三个建议 相辅相成的具体目标旨在澄清相互作用 在阿片剂和OFQ/LKC132神经肽递质系统之间。这个 包含在特定目标(1)中的实验旨在扩展我们的 在分子水平上了解OFQ/N神经肽系统。 具体地说，我们建议量化OFQ/N及其受体的变化 可能发生在对阿片类药物耐受的动物身上。我们还概述了设计的实验 我们发现的两种新的受体形式的特征 最后一次交接。包含在特定目标中的最后一组实验 描述了我们正在进行的努力，以生产出一种缺乏 OFQ/N受体。这些小鼠应该被证明是一个重要的动物模型 以此来评估OFQ/N受体系统在调节 阿片类药物耐受性、依赖性和奖赏。在具体目标(2)方面，我们有 建议的研究继续我们对OFQ/N的描述 腹侧明确神经元的电生理效应 被盖区。众所周知，这一领域在奖励方面很重要 已知动物的行为及其神经元会反复改变 暴露在吗啡中。具体目标(3)中提出的实验包括 某些神经解剖学底物的鉴定 OFQ/N的阿片类药物活动。这些微注射研究将为我们提供 用一种优雅的方法来确定Q/N的接受者是否能够 在药物幼稚的大鼠身上产生类似耐受性的效应。这些研究将 加深对Q/N参与阿片类药物镇痛的认识 耐受性，并最终可能导致改善疼痛和 上瘾。

DESCRIPTION (Applicant's Abstract): Opiates are powerful analgesic drugs. Unfortunately, their chronic use often results in addiction and tolerance, liabilities that seriously limit their clinical usefulness. Changes at the cellular and opiate receptor level have proven to be inadequate explanations of tolerance and dependcence. An exciting alternative hypothesis is that "anti-opioid" systems, neurotransmitters or neuropeptides that functionally oppose the effects of opiate receptor activation, contribute to tolerance and dependence as well as to variations in analgesic potency of opioids in some pathological pain states. We have recently demonstrated the orphanin FQ (OFQ, also referred to as nociceptin) is the endogenous ligand for the opioid-like G protein-coupled receptor LC132 and that it reverses morphine-induced analgesia, hypothermia and Straub tail. These anti-opioid actions of OFQ/N together with its close evolutionary kinship to endogenous opioid peptides suggesty that the OFQ/LC132 neurotransmitter system may play an important role in the homeostasis of opioid mechanisms. We propose three complimentary Specific Aims taht are designed to clarify the interactions between the opiate and the OFQ/LKC132 neuropeptide transmitter systems. The experiments included in Specific Aim (1) are designed to extend our knowledge about the OFQ/N neuropeptide system at the molecular level. Specifically we propose to quantitate changes in OFQ/N and its receptor that may occur in opiate-tolerant animals. We also outline experiments designed to characterize two new forms of the receptor that we discovered since ourr last subsmission. The last set of experiments included in Specific Aim described our ongoing efforts to produce a strain of mouse that lacks the OFQ/N receptor. These mice should prove to be an important animals model in which to evaluate the involvement of the OFQ/N receptor system in mediating opiate tolerance, dependence and reward. In Specific Aim (2) we have proposed studies that continue our characterization of OFQ/N's electrophysiological effects on well-defined neurons in the ventral tegmental area. This area of the is known to be important in reward behavior and its neurons are known to be altered in animals repeatedly exposeds to morphine. The experiments proposed in specific aim (3) involve the identification of some of the neuroanatomical substrates that mediate OFQ/N's ati-opioid activity. These microinjection studies will provide us with an elegant means by which to determine whetheer OFQ/N is able to produce a tolerance-like effect in drug-naive rats. These studies will advance our understanding OFQ/N's involvement in opioid analgesia as well as tolerance, and could ultmately lead to improved treatment of pain and addiction.