OPIOID RECEPTOR PHARMACOLOGY IN OPIATE ANESTHESIA

强效、短效的阿片类激动剂被广泛用于麻醉，因为 它们不会导致严重的心血管抑郁。而是深刻的 大剂量阿片类药物的镇痛作用伴随着强烈的全身性 肌肉僵硬和呼吸抑制。这些副作用 鸦片类药物严重限制了它们的临床价值。透彻地了解 阿片受体的药理作用(麻醉和镇痛) 和不受欢迎的(肌肉僵硬、呼吸抑制和滥用 潜在的)鸦片效应将对 阿片类镇痛药和无主要副作用麻醉药的研究进展 效果。拟议的实验旨在确定在大鼠身上：1) 哪种阿片受体介导阿片类药物诱导的肌肉僵直；2)哪种 阿片受体介导阿片类药物引起的呼吸抑制；3)什么 呼吸动力减弱与胸壁肌肉张力增加的作用 (由于肌肉僵硬)在呼吸抑制中发挥作用 大剂量阿片类药物；以及4)哪些阿片受体介导阿片类药物诱导 麻醉。需要解决的一个关键问题是，最重要的 大剂量阿片类药物给药(麻醉)的理想效果 从药理上与临床上最重要的两种药物分开 不良副作用(肌肉僵硬和呼吸抑制) 阿片受体特异性的基础。肌肉僵硬将是 通过测量后肢和后肢的肌电活动进行研究 腹肌。呼吸功能将使用两种方法进行评估： 室内体积描记术测量微小通气量和动脉使用量 血气分析。阿片类麻醉剂的评估标准是 翻正反射以及心率和对运动的反应 有害刺激(尾部压力)。三者的阿片受体药理学 将使用选择性激动剂和拮抗剂来检查效果。毒品 将被直接注入大脑的侧脑室。 这些实验将检验的主要假设是，理想的 鸦片类药物的作用(止痛和麻醉)将与 对心脏的不良影响(肌肉僵硬和呼吸抑制) 阿片受体药理学基础。数据将通过分析进行比较 对数剂量-反应曲线和效价比以评估相对 分离每个受体的合意和不合意的影响- 所研究的选择性药物。需要检验的第二个假设是 阿片类药物诱导的躯干强直对 大剂量阿片类药物后出现呼吸损害和酸中毒。这个 从这项工作中获得的阿片受体药理学知识将形成 开发和临床使用新阿片类药物的合理框架 毒品。

Potent, short-acting opiate agonists are widely used in anesthesia because they do not cause significant cardiovascular depression. But the profound analgesic effect of high-dose opiates is accompanied by intense generalized muscle rigidity and respiratory depression. These side effects of the opiates severely limit their clinical value. A thorough understanding of the opioid receptor pharmacology of desirable (anesthesia and analgesia) and undesirable (muscle rigidity, respiratory depression, and abuse potential) opiate effects will have important implications for the development of opiate analgesics and anesthetics without major side effects. The proposed experiments are designed to determine in rats: 1) which opioid receptors mediate opiate-induced muscle rigidity; 2) which opioid receptors mediate opiate-induced respiratory depression; 3) what role depressed respiratory drive versus increased chest wall muscle tone (due to muscle rigidity) plays in the respiratory depression seen with high-dose opiates; and 4) which opioid receptors mediate opiate-induced anesthesia. A key question to be addressed is whether the most important desirable effect of high dose opiate administration (anesthesia) can be pharmacologically separated from the two clinically most important undesirable side-effects (muscle rigidity and respiratory depression) on the basis of opioid receptor specificity. Muscle rigidity will be investigated by measuring the electromyographic activity from hindlimb and abdominal muscles. Respiratory function will be assessed using both dual- chamber plethysmography to measure minute ventilation and using arterial blood gases. Opiate anesthesia will be assessed by the absence of the righting reflex as well as by the heart rate and movement responses to a noxious stimulus (tail pressure). The opioid receptor pharmacology of each effect will be examined using selective agonists and antagonists. Drugs will be administered directly into the lateral ventricles of the brain. The main hypothesis these experiments will test is that the desirable effects of opiates (analgesia and anesthesia) will be separable from the undesirable effects (muscle rigidity and respiratory depression) on the basis of opioid receptor pharmacology. Data will be compared by analyzing log dose-response curves and potency ratios to assess the relative separation between desirable and undesirable effects for each receptor- selective drug studied. A secondary hypothesis to be tested will be that opiate-induced truncal rigidity contributes significantly to the respiratory compromise and acidosis seen after large opiate doses. The knowledge of opioid receptor pharmacology derived from this work will form a rational framework within which to develop and clinically use new opiate drugs.