OFQ MODULATION OF OPIOID EFFECTS

描述（申请人摘要）：阿片类药物是强效镇痛药。 不幸的是，长期使用它们往往会导致成瘾和耐受， 严重限制其临床应用的责任。 变动 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， “抗阿片样物质”系统、功能上 对抗阿片受体激活的影响，有助于耐受 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 FQ（OFQ，也称为伤害感受素）是神经递质的内源性配体。 阿片样G蛋白偶联受体LC 132，并逆转 吗啡诱导的镇痛、体温过低和斯特劳布尾。 这些抗阿片类药物 OFQ/N的作用以及其与内源性的密切进化亲缘关系 阿片肽可能与OFQ/LC 132神经递质系统有关 在阿片类药物机制的稳态中起重要作用。 我们提出了三 互补的具体目标旨在阐明相互作用 阿片和OFQ/LKC 132神经肽递质系统之间的联系。 的 具体目标（1）中包含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。 具体来说，我们建议定量OFQ/N及其受体的变化， 可能发生在阿片类药物耐受的动物身上。 我们还概述了实验设计 来描述我们发现的两种新的受体形式， 最后提交。 Specific Aim中包含的最后一组实验 描述了我们正在进行的努力，以产生一个品系的小鼠，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， 以评估OFQ/N受体系统在介导 阿片类药物耐受性、依赖性和奖赏。 在具体目标（2）中， 提出的研究继续我们的表征OFQ/N的 对腹侧明确神经元的电生理效应 被盖区 大脑的这一区域在奖赏方面很重要 众所周知，动物的行为及其神经元会反复改变 暴露在吗啡中 在具体目标（3）中提出的实验涉及 确定一些神经解剖学基质， OFQ/N的抗阿片活性。 这些显微注射研究将为我们提供 用一种优雅的方法来确定OFQ/N是否能够 在未用药的大鼠中产生耐受性样效应。 这些研究将 促进我们对OFQ/N参与阿片类镇痛的理解， 耐受性，并可能最终导致改善疼痛的治疗， 成瘾

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.