Milanés M V, Rabadan J V, Laorden M L
Department of Physiology and Pharmacology, University School of Medicine, Murcia, Spain.
Neuropeptides. 1997 Oct;31(5):511-5. doi: 10.1016/s0143-4179(97)90047-0.
The aim of the present investigation was to determine if chronic activation of kappa-opioid receptor induces development of tolerance and dependence to kappa-opioid agonists on the isolated right atrium of the rat. Tolerance to the kappa-agonist was induced by chronic administration of U-50,488H, a selective kappa-agonist (15 mg/kg i.p. twice a day for 4 days). The rats were killed on day 5. Tolerance to U-50,488H was observed after its chronic administration and was revealed as a rightward shift of the concentration-response curve; it was accompanied by a decrease in the maximum response and in the slope. Withdrawal to the kappa-agonist was induced by administration of Mr-2266 (preferentially kappa-antagonist) or nor-binaltorphimine (nor-bni; selective kappa-antagonist) to the organ bath. The administration of the kappa-antagonists Mr-2266 or nor-bni to preparations from tolerant rats in the organ bath induced an increase in auricular contraction frequency. In contrast, the administration of the kappa-antagonists to preparations from vehicle-treated rats induced a decrease in auricular contraction frequency. These findings demonstrate that the hearts of rats that had received chronic U-50,488H treatment develop tolerance to the cardiac effects of U-50,488H and exhibit excitatory reactions to kappa-antagonist's precipitated withdrawal.
本研究的目的是确定κ-阿片受体的慢性激活是否会诱导大鼠离体右心房对κ-阿片激动剂产生耐受性和依赖性。通过慢性给予选择性κ-激动剂U-50,488H（15mg/kg腹腔注射，每天两次，共4天）诱导对κ-激动剂的耐受性。在第5天处死大鼠。慢性给予U-50,488H后观察到对其产生耐受性，表现为浓度-反应曲线右移；同时最大反应和斜率降低。通过向器官浴中加入Mr-2266（优先为κ-拮抗剂）或去甲纳曲酮（nor-bni；选择性κ-拮抗剂）诱导对κ-激动剂的戒断反应。向器官浴中来自耐受性大鼠的制剂加入κ-拮抗剂Mr-2266或nor-bni会导致耳廓收缩频率增加。相反，向来自赋形剂处理大鼠的制剂加入κ-拮抗剂会导致耳廓收缩频率降低。这些发现表明，接受慢性U-50,488H治疗的大鼠心脏对U-50,488H的心脏效应产生耐受性，并对κ-拮抗剂诱发的戒断表现出兴奋反应。
