June H L, Grey C, Warren-Reese C, Durr L F, Ricks-Cord A, Johnson A, McCane S, Williams L S, Mason D, Cummings R, Lawrence A
Department of Psychology, Purdue School of Science, Indiana University-Purdue University, Indianapolis 46202-3275, USA.
Alcohol Clin Exp Res. 1998 Dec;22(9):2174-85.
Nalmefene, the 6-methylene derivative of naltrexone, was examined after subcutaneous (s.c.) (0.0001 to 8.0 mg/kg) and oral (10 to 80.0 mg/kg) administration in ethanol (EtOH)-preferring rats whose responding (i.e., lever pressing) was maintained by the presentation of EtOH. Naltrexone (0.01 to 40 mg/kg) was used as a reference opioid antagonist. EtOH (10% v/v) and saccharin (0.025 to 0.1% w/v) solutions were concurrently available for 1 hr each day under a two-lever, fixed-ratio schedule in which four responses on one lever produced the EtOH solution and four responses on the other lever produced the saccharin solution. When basal response rates for saccharin were 10% that of EtOH, all routes of nalmefene administration reduced control levels of responding maintained by EtOH by 38 to 84%. When basal response rates for saccharin-maintained responding were 60% or 82% that of EtOH, only lower s.c. naltrexone (e.g., 0.01 to 0.025 mg/kg) and nalmefene (e.g., 0.01 to 0.10 mg/kg) doses produced a selective dose-dependent suppression of EtOH-maintained responding. Higher nalmefene (0.25 to 8.0 mg/kg) and naltrexone (1.0 to 20.0 mg/kg) doses failed to produce a dose-dependent suppression on EtOH or saccharin maintained responding. Both antagonists suppressed responding maintained by EtOH primarily during the initial 10-min period, with little additional suppression occurring across the remainder of the 60-min period. Subcutaneous nalmefene was 3200- to 6400-fold more potent than oral nalmefene, suggesting bioavailability was optimized using the s.c. route. Nalmefene (0.5 mg/kg, s.c.) treatment for 10 consecutive days produced mild tolerance development, whose effects dissipated by day 8. Naltrexone (10 to 40 mg/kg) and nalmefene (1.5 to 3.0 mg/kg), given 8 to 24 hr before the test session, reduced control levels of responding maintained by EtOH by 82%. Thus, immediate opioid receptor occupancy was not required to observe antagonism. These data demonstrate that, under a variety of experimental conditions, nalmefene is an effective antagonist of responding maintained by EtOH and lend support to clinical reports that nalmefene may function as an alternative pharmacotherapy to naltrexone to reduce EtOH-motivated behavior and prevent relapse.
纳美芬是纳曲酮的6-亚甲基衍生物，在皮下注射（0.0001至8.0毫克/千克）和口服（10至80.0毫克/千克）给药后，对偏好乙醇（EtOH）的大鼠进行了研究，这些大鼠通过给予EtOH来维持其反应（即杠杆按压）。纳曲酮（0.01至40毫克/千克）用作参考阿片类拮抗剂。乙醇（10% v/v）和糖精（0.025至0.1% w/v）溶液每天同时提供1小时，采用双杠杆固定比率时间表，其中在一个杠杆上进行四次反应可产生乙醇溶液，在另一个杠杆上进行四次反应可产生糖精溶液。当糖精的基础反应率为乙醇的10%时，所有纳美芬给药途径使EtOH维持的反应控制水平降低了38%至84%。当糖精维持反应的基础反应率为乙醇的60%或82%时，只有较低的皮下注射纳曲酮（例如0.01至0.025毫克/千克）和纳美芬（例如0.01至0.10毫克/千克）剂量产生了对EtOH维持反应的选择性剂量依赖性抑制。较高的纳美芬（0.25至8.0毫克/千克）和纳曲酮（1.0至20.0毫克/千克）剂量未能对EtOH或糖精维持的反应产生剂量依赖性抑制。两种拮抗剂主要在最初的10分钟内抑制EtOH维持的反应，在剩余的60分钟内几乎没有额外的抑制作用。皮下注射纳美芬的效力比口服纳美芬高3200至6400倍，表明通过皮下注射途径生物利用度得到了优化。连续10天皮下注射纳美芬（0.5毫克/千克）会产生轻度耐受性，其作用在第8天消散。在测试前8至24小时给予纳曲酮（10至40毫克/千克）和纳美芬（1.5至3.0毫克/千克），可使EtOH维持的反应控制水平降低82%。因此，观察到拮抗作用并不需要立即占据阿片受体。这些数据表明，在各种实验条件下，纳美芬是EtOH维持反应的有效拮抗剂，并支持了临床报告，即纳美芬可能作为纳曲酮的替代药物疗法，以减少由EtOH驱动的行为并预防复发。
