NITRIC OXIDE AND MORPHINE PHYSICAL DEPENDENCE

这项研究的广泛、长期目标是确定 一氧化氮(NO)介导阿片类药物依赖。此应用程序侧重于 一氧化氮合酶(NOS)抑制剂和NO供体对血管内皮细胞的影响 吗啡对雄性大鼠的身体依赖。初步研究 提示一氧化氮合酶抑制剂的中枢抑制作用减弱 吗啡戒断的严重程度，没有捐赠者诱导吗啡- 抑制戒断症状，慢性一氧化氮合酶抑制诱导 一种类似吗啡的依赖。提出了两个具体的目标来测试 关于NO参与吗啡部分表达的假说 戒断和一氧化氮合酶抑制在一定程度上介导了 吗啡身体依赖： 首先，研究确定一氧化氮是否介导了吗啡的表达 戒断将通过给雄性大鼠植入吗啡来实现 慢性给药丸，然后给药NO相关的组合 在纳洛酮-或没有供体-之后，药物和禁欲体征的测量 突然戒断，或在突然的、自发的戒断之后。 第二，关于一氧化氮合酶抑制介导血管紧张素转换酶发生的假说 将在以下方面测试吗啡的身体依赖性：(1)慢性吗啡 研究，(2)慢性一氧化氮合酶抑制研究，和(3)研究测量 吗啡水平。这些实验将包括纳洛酮-和/或没有- 在几种药物组合后突然戒断或自发戒断 检查阿片类药物和一氧化氮系统如何相互作用的治疗 依赖发展。治疗将包括(1)慢性吗啡 填充了一氧化氮合酶抑制剂或一氧化氮合酶的小球和渗透泵 底物，和(2)长期重复注射吗啡，一种一氧化氮合酶 抑制剂、一氧化氮合酶底物和一氧化氮供体，然后采取措施 戒断程度和吗啡生物处置。 该项目与健康相关的内容包括 一氧化氮作用的新的生理和病理机制 阿片类药物效应，可能为治疗和治疗提供新的理论依据 预防阿片类药物滥用和戒断以及改进 阿片类药物的医疗用途。

The broad, long-term objective of this research is to determine if nitric oxide (NO) mediates opioid dependence. This application focuses on the effects of NO synthase (NOS) inhibitors and NO donors on morphine physical dependence in male rats. Preliminary studies indicated that central depressant actions of NOS inhibitors decrease the severity of morphine withdrawal, that NO donors induce morphine- suppressed withdrawal signs, and that chronic NOS inhibition induces a morphine-like dependence. Two specific aims are proposed to test the hypothesis that NO mediates part of the expression of morphine withdrawal and that NOS inhibition mediates part of the development of morphine physical dependence: First, studies to determine if NO mediates the expression of morphine abstinence will be carried out by implanting male rats with morphine pellets chronically, then administering combinations of NO-related agents and measuring abstinence signs after naloxone- or NO donor- precipitated withdrawal, or after abrupt, spontaneous withdrawal. Second, the hypothesis that NOS inhibition mediates the development of morphine physical dependence will be tested in: (1) chronic morphine studies, (2) chronic NOS inhibition studies, and (3) studies measuring morphine levels. These experiments will include naloxone- and/or NO- precipitated or spontaneous withdrawal after several combinations of treatments to examine how the opioid and NO systems interact in dependence development. Treatments will include (1) chronic morphine pellets and osmotic pumps filled with a NOS inhibitor or NOS substrates, and (2) chronic repeated administration of morphine, a NOS inhibitor, NOS substrates, and a NO donor followed by measures of withdrawal severity and morphine biodisposition. The health relatedness of this project includes the characterization of new physiological and pathological mechanisms of action of NO in opioid effects that may suggest new rationales for the treatment and prevention of opioid abuse and withdrawal and improvements in the medical use of opioids.