PHARMACOLOGY OF OPIOID RECEPTOR SUBTYPES

阿片类药物对治疗疼痛很重要，但滥用阿片类药物会导致 一个主要的健康问题，由于他们与最近的艾滋病毒 疫情 了解阿片类药物在体内的作用对他们的治疗至关重要。 临床合理使用和潜在治疗方法的开发 虐待阿片类药物和阿片肽通过一个受体家族起作用， 其中至少有三种阿片受体已被克隆：μ，δ和 kappa1.对这些受体在组织中作用的研究 文化提供了关于它们的生物化学的重要信息 第二信使系统然而，这种方法无法解决许多问题。 关于它们在综合神经系统中的作用的问题。的 本申请提出探索这些受体的作用 vivo.反义方法将被用来关联克隆的阿片样物质 受体与阿片类药物我们实验室的初步研究 证明针对人肝癌细胞的反义寡核苷酸（ODN）， δ、μ或κ 1受体选择性和特异性下调 而不干扰其他受体的功能。 不匹配的ODN控件处于非活动状态。这种方法将得到验证， 观察各种ODN在组织培养中的吸收和稳定性， 以及建立优化其使用的标准。 反义寡核苷酸将被用来检查负责的受体， 多种阿片类药物作用，包括镇痛、呼吸抑制 和抑制胃肠转运。的第二组分 本申请解决了公差问题。这项工作将扩大 根据以前的观察，NMDA拮抗剂和一氧化氮合酶 (NOS)抑制剂可以预防或逆转吗啡耐受。额外 将使用基因敲除法检查药物，并研究NOS的作用。 老鼠.最后，在阿片类镇痛中重要的区域相互作用将 被探索。阿片类药物通过激活多个大脑和 脊椎骨同时这些相互作用以及 将探讨协同作用。研究表明，内在脑干 协同作用将扩大，更多的实验将探索 我们小组最近观察到脑干区域之间的mu/delta协同作用。 总的来说，这项提案将提供重要的信息， 阿片受体分子生物学的最新进展， 药理学

Opiates are important for the treatment of pain, but their abuse presents a major health problem due to their association with the recent HIV epidemic. Understanding the actions opiates in vivo is crucial to their rational use clinically and the development of potential treatments for abuse. Opiates and the opioid peptides act through a family of receptors, of which at least three opioid receptors have been cloned: mu, delta and kappa1. Studies on the actions of these receptors carried out in tissue culture have provided important information regarding their biochemistry and second messenger systems. However, this approach cannot address many questions regarding their actions within an integrated nervous system. The current application proposes to explore the actions of these receptors in vivo. Antisense approaches will be utilized to correlate the cloned opioid receptors with opioid pharmacology. Initial studies from our laboratory demonstrate that antisense oligodeoxynucleotides (ODN) directed against delta, mu or kappa1 receptors selectively and specifically downregulate their own receptor without interfering the function of the others. Mismatch ODN controls are inactive. This approach will be validated, looking at the uptake and stability of the various ODN's in tissue culture and in vivo as well as establishing the criteria to optimize their use. Antisense ODN's then will be used to examine the receptors responsible for a variety of opioid actions, including analgesia, respiratory depression and the inhibition of gastrointestinal transit. The second component of this application addresses the issue of tolerance. This work will expand on previous observations that NMDA antagonists and nitric oxide synthase (NOS) inhibitors can prevent or reverse morphine tolerance. Additional agents will be examined and the role of NOS studied using a knockout mouse. Finally, regional interactions important in opioid analgesia will be explored. Opiates act through the activation of multiple brain and spinal regions simultaneously. These interactions and the existence of synergy will be explored. Studies demonstrating intrinsic brainstem synergy will be expanded and additional experiments will explore the mu/delta synergy between brainstem regions recently observed by our group. Overall, this proposal will provide important information correlating recent advances in the molecular biology of opioid receptors with their pharmacology.