Aksu F, Holmes B B, Fujimoto J M
Research Service-151, Veterans Administration Medical Center, Milwaukee, WI.
Pharmacol Biochem Behav. 1993 Jun;45(2):409-18. doi: 10.1016/0091-3057(93)90258-u.
Naloxone and norbinaltorphimine when given ICV to mice can antagonize IT morphine-induced analgesia indirectly by releasing spinal dynorphin A(1-17) (Dyn A). Dyn A produces an antianalgesic action against IT morphine. In the present study, drugs with varying amounts of opioid antagonist to agonist action (nalbuphine, levallorphan, naltrexone, and naltrindole) were given ICV to determine whether they antagonized IT morphine-induced inhibition of the tail-flick response as an indication of spinal Dyn A release. Additional pharmacological tests were used as criteria for Dyn A release: a) Small doses of the opioid antagonists naloxone and norbinaltorphimine administered IT inhibited the antagonistic action; b) dynorphin antiserum given IT blocked the action of Dyn A; c) desensitization to the effect of Dyn A was produced by 3-h pretreatment with morphine, 10 mg/kg SC, or by pretreatment with the agents themselves. When given ICV, nalbuphine, levallorphan, and naltrexone released Dyn A in the spinal cord to produce an antianalgesic effect. Naltrindole, a delta-receptor antagonist, did not release Dyn A. Dyn A release did not appear to involve delta-receptors. Thus, a number of opioid antagonists inhibit the analgesic action of opioid agonists indirectly through Dyn A release.
当向小鼠脑室内注射纳洛酮和去甲二氢吗啡酮时，它们可通过释放脊髓强啡肽A（1-17）（Dyn A）间接拮抗脑室内注射吗啡诱导的镇痛作用。Dyn A对脑室内注射吗啡产生抗镇痛作用。在本研究中，向小鼠脑室内注射具有不同阿片类拮抗剂与激动剂作用比例的药物（纳布啡、左洛啡烷、纳曲酮和纳曲吲哚），以确定它们是否拮抗脑室内注射吗啡诱导的甩尾反应抑制，以此作为脊髓Dyn A释放的指标。还采用了其他药理学试验作为Dyn A释放的标准：a）脑室内注射小剂量阿片类拮抗剂纳洛酮和去甲二氢吗啡酮可抑制这种拮抗作用；b）脑室内注射强啡肽抗血清可阻断Dyn A的作用；c）皮下注射10 mg/kg吗啡预处理3小时或用这些药物本身预处理可产生对Dyn A作用的脱敏。当脑室内注射时，纳布啡、左洛啡烷和纳曲酮可在脊髓中释放Dyn A以产生抗镇痛作用。δ受体拮抗剂纳曲吲哚不释放Dyn A。Dyn A的释放似乎不涉及δ受体。因此，一些阿片类拮抗剂通过释放Dyn A间接抑制阿片类激动剂的镇痛作用。
