DYNORPHIN A MODULATES OPIOIDS VIA A NOVEL DYN RECEPTOR

强啡肽A（1-17）是一种内源性阿片肽， 但大量证据表明，它也通过非- 阿片系统例如，它抑制醋酸引起的扭体， 纳洛酮不拮抗这种作用，并抑制 吗啡耐受动物的吗啡耐受和依赖。 此外，这两种作用也由des-Tyr肽介导， 强啡肽A（2-17），其没有阿片样物质活性并且不结合 阿片受体 最近，我们获得了强啡肽A（2-17）结合其 拥有独特的非阿片受体。本提案旨在 检验强啡肽的非阿片类作用的假设， 特别是其对阿片样物质耐受性/依赖性的调节 通过这些受体。为了验证这一假设，我们将1）描述 详细介绍了其药理学和生物化学性质， 强啡肽A（2-17）结合位点，我们最近发现， 脑、脊髓和背根神经节; 2）纯化和cDNA克隆 强啡肽A受体（2-17）; 3）确定改变 内源性强啡肽水平，使用抗强啡肽抗体， 在不同程度的小鼠品系中的耐受性发展 他们开发的耐受性;和4）寻找多态性差异， 阿片受体，可能解释能力的差异， 强啡肽来调节这些阿片受体的作用。 总体而言， 这个建议是为了测试一个新的假设， 一个未知的dynA（2-17）受体系统，可能在阿片类药物中发挥作用 宽容

APPLICANT'S ABSTRACT: DynorphinA(1-17) is an endogenous opioid peptide, but considerable evidence indicates that it also acts through a non- opioid system. For example, it inhibits acetic acid-induced writhing, an effect not antagonized by naloxone, and inhibits the expression of morphine tolerance and dependence in morphine tolerant animals. Moreover, both these effects are also mediated by the des-Tyr peptide, dynorphinA(2-17), which has no opioid activity and does not bind to opioid receptors. Recently, we have obtained evidence that dynorphinA(2-17) binds to its own distinct, non-opioid receptors. The present proposal is designed to test the hypothesis that the non-opioid effects of dynorphin, in particular, its modulation of opioid tolerance/dependence, are mediated through these receptors. To test this hypothesis, we will 1) characterize in detail the pharmacological and biochemical properties of dynorphinA(2-17) binding sites which we have recently identified in brain, spinal cord and dorsal root ganglia; 2) purify and cDNA clone the receptor for dynorphinA(2-17); 3) determine the effect of altering endogenous levels of dynorphin, using anti-dynorphin antibodies, on tolerance development in strains of mice differing in the degree of tolerance they develop; and 4) search for polymorphic differences in opioid receptors that might account for differences in the ability of dynorphin to modulate the actions of these opioid receptors. Overall, this proposal is designed to test a novel hypothesis of the existence of a yet unknown dynA(2-17) receptor system which may play a role in opioid tolerance.