Duttaroy A, Billings B, Candido J, Yoburn B C
Department of Pharmaceutical Sciences, College of Pharmacy, St. John's University, Queens, NY 11439.
Eur J Pharmacol. 1992 Oct 20;221(2-3):211-5. doi: 10.1016/0014-2999(92)90703-7.
Chronic treatment with an opioid antagonist, such as naltrexone, increases opioid receptor density and opioid agonist potency. Since stimulants such as d-amphetamine can increase opioid potency and opioid abusers may administer stimulants during naltrexone treatment, the effect of chronic d-amphetamine on naltrexone-induced opioid receptor upregulation and supersensitivity was examined in mice. Mice were implanted s.c. with a 15 mg naltrexone or placebo pellet for 8 days. Mice were injected daily with saline or d-amphetamine (7.5 or 5.0 mg/kg per day s.c.) for 7 days beginning 24 h following implantation. Naltrexone and placebo pellets were removed on the 8th day, and 24 h later mice were tested for morphine analgesia (tail-flick) or whole brain was removed and opioid receptor binding studies were conducted. Chronic naltrexone significantly enhanced the analgesic potency of morphine in saline-treated mice. However, naltrexone treatment did not increase morphine potency in mice treated with d-amphetamine. In binding studies, naltrexone increased [3H][D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO) Bmax (+60-70%) without altering KD in both saline- and d-amphetamine-treated mice. Results from studies with 2 nM [3H][D-Pen2,D-Pen5]enkephalin (DPDPE) were similar. These studies indicate that daily d-amphetamine can limit naltrexone-induced supersensitivity but not receptor upregulation. Thus, upregulation can be dissociated from functional supersensitivity.
使用阿片类拮抗剂（如纳曲酮）进行长期治疗会增加阿片受体密度和阿片激动剂效力。由于兴奋剂（如右旋苯丙胺）可增加阿片效力，且阿片类药物滥用者在纳曲酮治疗期间可能会使用兴奋剂，因此研究了慢性右旋苯丙胺对纳曲酮诱导的阿片受体上调和超敏反应的影响。给小鼠皮下植入15毫克纳曲酮或安慰剂药丸，持续8天。从植入后24小时开始，每天给小鼠皮下注射生理盐水或右旋苯丙胺（7.5或5.0毫克/千克/天），持续7天。在第8天取出纳曲酮和安慰剂药丸，24小时后测试小鼠的吗啡镇痛作用（甩尾法），或取出全脑进行阿片受体结合研究。慢性纳曲酮显著增强了生理盐水处理小鼠中吗啡的镇痛效力。然而，纳曲酮治疗并未增加右旋苯丙胺处理小鼠中吗啡的效力。在结合研究中，纳曲酮增加了[3H][D - 丙氨酸2，N - 甲基苯丙氨酸4，甘氨酸 - 醇5]脑啡肽（DAGO）的最大结合容量（+60 - 70%），而在生理盐水和右旋苯丙胺处理的小鼠中均未改变解离常数。使用2 nM [3H][D - 青霉胺2，D - 青霉胺5]脑啡肽（DPDPE）的研究结果相似。这些研究表明，每日右旋苯丙胺可限制纳曲酮诱导的超敏反应，但不能限制受体上调。因此，上调可与功能性超敏反应分离。
