MECHANISMS OF CONDITIONED TOLERANCE TO MORPHINE

吗啡条件耐受机制

• 批准号: 2116649
• 负责人: CLAIRE D ADVOKAT
• 金额: $ 10.35万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2116649
• 关键词: acetylcholine; adenosine; analgesics; brain stem transection; centrally acting drug; drug addiction antagonist; drug administration rate /duration; drug administration routes; drug metabolism; drug tolerance; endogenous opioid; gamma aminobutyrate; glutamates; laboratory rat; microinjections; morphine; neuropharmacology; neurotransmitters; norepinephrine; opiate alkaloid; pain; radioimmunoassay; serotonin; spinal cord; stimulant /agonist; stimulus /response

The long-term objective of this research is to understand how morphine acts acutely in the central nervous system to produce analgesia and how these effects are modified by chronic pain and/or morphine exposure, to produce tolerance. Previous investigations led to a model, which postulates that 1) the analgesic effect of morphine at the spinal cord is normally suppressed by a mechanism originating in the brain, and that 2) this suppression is eliminated when the spinal cord is transected or when morphine is simultaneously administered to the brain and the spinal cord. The removal of this inhibitory influence on the spinal effect of morphine accounts for the profound potency of systemically administered morphine relative to the effect of morphine at each of these two sites separately. The specific aim of the proposed experiments is to determine which transmitter(s) are responsible for the postulated inhibition exerted by the brain on the analgesic effect of spinal morphine. Representative agonists and antagonists of several transmitter systems will be administered to the spinal cord (intrathecally) of intact rats and rats that have received an acute spinal transection. These compounds will be injected 1)alone - to determine whether they are directly involved in pain (nociceptive) processes at the level of the spinal cord and 2) in combination with a) spinal morphine b) spinal and supraspinal morphine and c) systemic morphine - to determine whether they modulate opiate analgesia. The nociceptive response will consist of the tail withdrawal reflex (tail flick) to a noxious thermal stimulus. The transmitter systems that will be examined include the 1) opioids 2) adenosine 3) gamma-amino butyric acid 4) glutamate 5) acetylcholine 6) serotonin and 7) norepinephrine. If morphine-induced analgesia is modified, as predicted, by compounds that act through any of these systems, then our knowledge of opiate analgesia will be enhanced and subsequent studies can explore the role of these transmitters in opiate tolerance.

这项研究的长期目标是了解吗啡 在中枢神经系统中敏锐地起作用以产生镇痛以及如何 这些影响通过慢性疼痛和/或吗啡暴露来改变 产生公差。 以前的调查导致了模型，该模型 假设1）吗啡在脊髓上的镇痛作用为 通常被源自大脑的机制抑制，该机制2） 当脊髓转移或何时，消除了这种抑制 吗啡同时给予大脑和脊髓。 去除这种抑制作用对吗啡的脊柱效应 说明了系统管理的吗啡的深刻效力 相对于吗啡在这两个位点中的每个位点的影响。 拟议实验的具体目的是确定 发射机负责由 大脑对脊柱的镇痛作用。 代表 几个发射机系统的激动剂和对手将是 用于完整大鼠和大鼠的脊髓（鞘内） 接受了急性脊柱横断。 这些化合物将是 注射1）单独 - 确定它们是否直接参与 脊髓水平的疼痛（伤害性）过程，2） 与a）脊髓b）脊柱和上脊髓上吗啡的结合 c）系统性吗啡 - 确定它们是否调节鸦片 镇痛。 伤害性响应将包括尾巴提取 反射（尾部轻弹）对有害的热刺激。 发射器 将检查的系统包括1）阿片类药物2）腺苷3） γ-氨基丁酸4）谷氨酸5）乙酰胆碱6）5-羟色胺和 7）去甲肾上腺素。 如果将吗啡诱导的镇痛修饰，如 通过通过这些系统作用的化合物预测，我们 鸦片镇痛的知识将得到增强，随后的研究可以 探索这些发射机在阿片类药物耐受性中的作用。