DYNORPHIN A MODULATES OPIOIDS VIA A NOVEL DYN RECEPTOR

申请人摘要：强啡肽A(1-17)是一种内源性阿片肽， 但大量证据表明，它还通过一种非 阿片系统。例如，它可以抑制醋酸诱导的扭体，以及 作用不被纳洛酮拮抗，并抑制血管紧张素转换酶 吗啡耐受动物对吗啡的耐受和依赖。 此外，这两种作用也都是由Des-Tyr多肽介导的， 强啡肽A(2-17)，没有阿片类药物活性，不结合 阿片受体。 最近，我们获得了强啡肽A(2-17)与其结合的证据 拥有独特的非阿片受体。本提案的目的是 检验强啡肽的非阿片类药物作用的假设 尤其是它对阿片耐受/依赖的调节。 通过这些受体。为了检验这一假设，我们将1)描述 详细介绍了其药理和生化特性。 强啡肽A(2-17)结合位点，我们最近在 脑、脊髓和背根神经节；2)纯化并克隆 强啡肽A受体(2-17)；3)确定改变的效果 内源性强啡肽水平，使用抗强啡肽抗体， 不同耐受程度小鼠品系的耐受性发展 他们形成的耐受性；以及4)在 阿片受体，这可能解释了能力的差异 强啡肽来调节这些阿片受体的活动。总的来说， 这一提议旨在检验一种新的假设，即存在 一种未知的可能在阿片类药物中发挥作用的DyNA(2-17)受体系统 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.