Preston K L, Umbricht A, Schroeder J R, Abreu M E, Epstein D H, Pickworth W B
National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, USA.
Behav Pharmacol. 2004 Mar;15(2):91-102. doi: 10.1097/00008877-200403000-00001.
Kappa-opioid agonists produce neurobiological and behavioral effects opposite to those of cocaine and may be useful for the treatment of cocaine dependence. To evaluate the kappa- and mu-agonist effects of cyclazocine and to test whether cyclazocine pretreatment would attenuate the effects of cocaine, healthy, male and female, experienced opiate and cocaine users (n = 13) were enrolled in a two-phase study. In Phase 1, placebo, cyclazocine (0.2, 0.4 and 0.8 mg) and the mu-agonist hydromorphone (5 and 15 mg) were administered orally in six 4.5-hour sessions separated by at least 72 h. In Phase 2, cocaine (100 mg intranasal) was given 2 h after oral pretreatment with cyclazocine (0, 0.1, 0.2, 0.4, 0.8 and 0 mg, in that order) in each of six sessions conducted daily Monday to Friday and the following Monday. Physiological, subjective and behavioral measures were collected in each session. Nine participants completed Phase 1; eight completed Phase 2. Hydromorphone (15 mg) produced prototypic mu-agonist effects. Cyclazocine exhibited only modest kappa-like effects. Cyclazocine also had only modest, non-dose-related effects on response to cocaine. However, cocaine effects were consistently lower on the last administration (cyclazocine 0 mg pretreatment) following 4 days of cyclazocine pretreatment, compared to the first administration (0 mg pretreatment). This finding is unlikely to be fully attributable to cocaine tolerance and is not accounted for by pharmacokinetic changes; plasma concentrations of cocaine were not altered by cyclazocine. This study is suggestive but not strongly supportive for the use of kappa-opiate drugs to diminish acute effects of cocaine administration or for the use of these kappa agonists in drug abuse treatment applications.
κ-阿片受体激动剂产生与可卡因相反的神经生物学和行为效应，可能对治疗可卡因成瘾有用。为了评估环唑辛的κ-和μ-激动剂效应，并测试环唑辛预处理是否会减弱可卡因的效应，招募了健康的、有阿片类药物和可卡因使用经验的男性和女性使用者（n = 13）参与一项两阶段研究。在第1阶段，安慰剂、环唑辛（0.2、0.4和0.8毫克）和μ-激动剂氢吗啡酮（5和15毫克）在六个4.5小时的疗程中口服给药，疗程间隔至少72小时。在第2阶段，在周一至周五以及接下来的周一每天进行的六个疗程中，在口服环唑辛（依次为0、0.1、0.2、0.4、0.8和0毫克）预处理2小时后给予可卡因（100毫克鼻内给药）。在每个疗程中收集生理、主观和行为指标。9名参与者完成了第1阶段；8名完成了第2阶段。氢吗啡酮（15毫克）产生了典型的μ-激动剂效应。环唑辛仅表现出适度的κ样效应。环唑辛对可卡因反应也仅有适度的、与剂量无关的效应。然而，与首次给药（0毫克预处理）相比，在环唑辛预处理4天后的最后一次给药（环唑辛0毫克预处理）时，可卡因效应始终较低。这一发现不太可能完全归因于可卡因耐受性，也不能用药物动力学变化来解释；环唑辛未改变可卡因的血浆浓度。这项研究对于使用κ-阿片类药物减轻可卡因给药的急性效应或在药物滥用治疗应用中使用这些κ-激动剂具有一定的提示作用，但支持力度不强。
