Spanagel R, Shoaib M
Department of Neuroendocrinology, Max Planck Institute of Psychiatry, Clinical Institute, Munich, Germany.
Neuroscience. 1994 Dec;63(3):797-804. doi: 10.1016/0306-4522(94)90524-x.
The neuroanatomical basis of opiate addiction has been studied using a variety of behavioural techniques. The aim of the present study was to investigate the role of mesolimbic opioid systems, in particular kappa-opioid systems, in the expression of the discriminative stimulus effects of abused drugs. Rats were trained to discriminate morphine (3.0 mg/kg s.c.) from saline under a fixed ratio schedule of food reinforcement. Once rats had acquired the discrimination, a randomized sequence of different doses of the highly selective kappa-opioid receptor agonist U69593 (0.02-0.16 mg/kg s.c.) was given 20 min prior to a systemic morphine injection. U69593 dose-dependently blocked the morphine discrimination. It is important to note that U69593 at these doses failed to generalize to the systemic morphine cue. The site of action by U69593 (0.02-0.16 microgram) was examined by microinjecting discrete amounts into target brain regions. Intra-nucleus accumbens injections of U69593 dose-dependently blocked the systemic morphine cue, whereas, U69593 failed to generalize to the discriminative stimulus. The same doses did not affect morphine discrimination after intra-ventral tegmental area or striatum injections. Besides the rewarding effects of drugs of abuse, the discriminative stimulus properties of these agents are seen as a major factor in drug seeking behaviours. The present study shows that the discriminative effects of morphine, a measure of the subjective effects of this drug can be blocked by the activation of kappa-opioid receptors located in the nucleus accumbens. In view of these findings which show that the activity of endogenous potassium-opioid systems (dynorphin) may serve as physiological antagonists to counteract the effects of morphine, potassium-agonists therefore may be useful in the treatment of opioid addictions.
人们已运用多种行为学技术对阿片类成瘾的神经解剖学基础展开研究。本研究旨在探讨中脑边缘阿片系统，尤其是κ-阿片系统，在滥用药物辨别刺激效应表达中的作用。在固定比率食物强化程序下，训练大鼠区分皮下注射的吗啡（3.0毫克/千克）和生理盐水。大鼠一旦学会这种辨别，在全身注射吗啡前20分钟，给予不同剂量的高选择性κ-阿片受体激动剂U69593（0.02 - 0.16毫克/千克，皮下注射）的随机序列。U69593呈剂量依赖性地阻断吗啡辨别。需注意的是，这些剂量的U69593未能泛化至全身吗啡线索。通过向目标脑区微量注射不同剂量的U69593（0.02 - 0.16微克）来检测其作用位点。向伏隔核内注射U69593呈剂量依赖性地阻断全身吗啡线索，然而，U69593未能泛化至辨别刺激。相同剂量在腹侧被盖区或纹状体注射后不影响吗啡辨别。除了滥用药物的奖赏效应外，这些药物的辨别刺激特性被视为药物寻求行为的一个主要因素。本研究表明，吗啡的辨别效应（该药物主观效应的一种度量）可被伏隔核中κ-阿片受体的激活所阻断。鉴于这些发现表明内源性κ-阿片系统（强啡肽）的活性可能作为生理拮抗剂来抵消吗啡的作用，κ-激动剂因此可能对阿片类成瘾的治疗有用。
