Kalso E A, Sullivan A F, McQuay H J, Dickenson A H, Roques B P
Department of Pharmacology, University College London, United Kingdom.
J Pharmacol Exp Ther. 1993 May;265(2):551-8.
Intrathecal administration of morphine, Tyr-D-Ser(otbu)-Gly-Phe-Leu-Thr or dexmedetomidine for 5 to 10 days rendered rats tolerant to the test drug as measured by both behavioral and electrophysiological tests. Tolerance to the alpha-2 adrenergic agonist dexmedetomidine required a longer induction time and was not as pronounced as the tolerance to the opioid agonists, probably because lower doses of dexmedetomidine relative to the ED50 dose were used to avoid sedation. In the behavioral studies we used the tail-flick test and in the electrophysiological studies recordings were made from dorsal horn nociceptive neurons under halothane anesthesia. After completion of the behavioral testing the same animals were then used in the electrophysiological study. Cross-tolerance developed clearly between the mu opioid agonist morphine and the alpha-2 adrenergic agonist dexmedetomidine, whereas no cross-tolerance was seen between the delta opioid agonist Tyr-D-Ser(otbu)-Gly-Phe-Leu-Thr and either morphine or dexmedetomidine. This is further evidence to support the assumption that in the dorsal horn the mu opioid and the alpha-2 adrenergic receptor are linked functionally, whereas the delta opioid receptor operates independently. These results have also important clinical implications indicating the potential of delta opioid agonists to restore analgesia in a morphine-tolerant patient.
鞘内注射吗啡、酪氨酰-D-丝氨酸（叔丁酯）-甘氨酰-苯丙氨酰-亮氨酰-苏氨酸或右美托咪定5至10天，通过行为学和电生理学测试发现大鼠对受试药物产生了耐受性。对α2肾上腺素能激动剂右美托咪定的耐受性需要更长的诱导时间，且不如对阿片类激动剂的耐受性明显，这可能是因为相对于ED50剂量，使用了较低剂量的右美托咪定以避免镇静作用。在行为学研究中，我们使用了甩尾试验，在电生理学研究中，在氟烷麻醉下从背角伤害性神经元进行记录。行为学测试完成后，将相同的动物用于电生理学研究。μ阿片类激动剂吗啡和α2肾上腺素能激动剂右美托咪定之间明显产生了交叉耐受性，而δ阿片类激动剂酪氨酰-D-丝氨酸（叔丁酯）-甘氨酰-苯丙氨酰-亮氨酰-苏氨酸与吗啡或右美托咪定之间均未观察到交叉耐受性。这进一步证明了以下假设：在背角，μ阿片类和α2肾上腺素能受体在功能上相联系，而δ阿片类受体独立发挥作用。这些结果也具有重要的临床意义，表明δ阿片类激动剂有可能恢复吗啡耐受患者的镇痛效果。
