KAPPA-RECEPTORS MEDIATE THE PERIPHERAL AVERSIVE EFFECTS OF OPIATES
KAPPA-RECEPTORS MEDIATE THE PERIPHERAL AVERSIVE EFFECTS OF OPIATES
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DOI：
10.1016/0091-3057(87)90219-x
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发表时间：
1987-10-01
影响因子：
3.6
通讯作者：
VANDERKOOY, D
中科院分区：
文献类型：
--
作者：
BECHARA, A;VANDERKOOY, D
以往的证据表明，内源性和外源性阿片类药物通过作用于中枢神经系统阿片受体产生积极的增强效应，而通过作用于外周阿片受体产生厌恶效应。为了探讨阿片厌恶效应对外周阿片受体亚型的药理学特异性，药物初生鼠皮下或腹腔注射不同剂量的Kappa受体激动剂U50,488(0.005-16 mg/kg)，并在位置条件反射模式下运行。这些结果与之前发表的关于吗啡的激励作用的数据进行了比较，这些数据是使用相同的实验程序收集的[1]。不管给药途径如何，大多数剂量的U50,488产生条件性位置厌恶，而增加剂量的吗啡产生条件性位置偏爱[1]。只有小剂量的吗啡(腹腔注射0.05 mg/kg，皮下注射)才能产生明显的位置厌恶，提示局部肠道效应[1]。迷走神经切断术阻断了吗啡的厌恶特性[1]，并在本报告中将中等剂量的U50,488的兴奋效应转变为偏好。U50,488产生厌恶的剂量比产生厌恶效应的小剂量吗啡低5倍。即使在非常高的剂量下，U50,488也不会产生与吗啡一样的条件性位置偏爱。这些由U50,488引起的高剂量厌恶可被低剂量的kappa拮抗剂MR2266所减弱。为了研究外周内源性kappa激动剂的可能作用，在位置条件反射范式中，对不同剂量的幼鼠注射不同剂量的特定kappa拮抗剂MR2266(0.001-10 mg/kg)或其非活性异构体MR2267(0.01-10 mg/kg)，绘制了剂量-反应曲线。将结果与之前发表的关于纳曲酮(0.01-10 mg/kg)[1]的数据进行了比较，这些数据是通过相同的实验程序收集的。在低剂量下产生偏好的能力是纳曲酮的10倍。不活跃的异构体Mr 2267在产生地点偏爱方面比Mr 2266有效的剂量无效。这些结果表明，外源性和内源性阿片类药物的厌恶效应的主要部位是外周kappa受体。
Previous evidence has suggested that endogenous and exogenous opioids produce positive reinforcing effects through an action on central nervous system opiate receptors and aversive effects through an action on peripheral opiate receptors. In order to investigate that pharmacological specificity of the opiate aversive effects to peripheral opiate receptor subtypes, drug naive rats were administered various subcutaneous or intraperitoneal dose of the specific kappa receptor agonist U50,488 (0.005-16 mg/kg) and run in a place conditioning paradigm. The results were compared to previously published data on the motivational effects of morphine, collected using identical experimental procedures [1]. Regardless of the route of administration, the majority of doses of U50,488 produced conditioned place aversions, whereas increasing doses of morphine produced conditioned place preferences [1]. Only a low dose of morphine (0.05 mg/kg intraperitoneally but not subcutaneously) was shown to produce significant place aversions, suggesting a local gut effect [1]. Vagotomy blocked the aversive properties of morphine [1], and in the present report shifted the motivational effects of moderate doses of U50,488 into preferences. U50,488 produced aversions at a dose that was 5 times lower than the low dose of morphine that produced aversive effects. Even at very high doses, U50,488 did not produce the conditioned place preferences seen with morphine. These high dose aversions induced by U50,488 were attenuated by a low intraperitoneal dose of the kappa antagonist Mr2266. In order to investigate the possible actions of peripheral, endogenous kappa agonists, a dose-response curve was generated in the place conditioning paradigm from separate groups of naive rats injected with various intraperitoneal doses of the specific kappa antagonist Mr2266 (0.001-10 mg/kg) or its inactive isomer Mr2267 (0.01-10 mg/kg). The results were compared to previously published data on naltrexone (0.01-10 mg/kg) [1], collected using identical experimental procedures. Mr2266 was 10 times more potent than naltrexone in producing preferences at low doses. The inactive isomer, Mr2267 was ineffective in producing place preferences over the doses at which Mr2266 was effective. The results suggest that the primary site of the aversive effects of both exogenous and endogenous opioids is the peripheral kappa receptor.