Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Department of Addictions, St. Petersburg Bekhterev Research Psychoneurological Institute, St. Petersburg, Russia.
Addict Biol. 2018 May;23(3):945-958. doi: 10.1111/adb.12538. Epub 2017 Jul 25.
The gabapentinoid pregabalin is a rapid-acting anxiolytic and analgesic, possibly suitable in supervised opioid detoxification. However, clinicians have been cautious in using it because of its unknown addictive risk and rising number of mortalities after pregabalin self-medication in opioid abusers. Here, we studied interactions of pregabalin and morphine on reward functions of the dopamine system in mice and the efficacy of pregabalin on withdrawal in opioid addicts. After the treatment of mice with pregabalin and morphine, we used electrophysiology to study neuroplasticity in midbrain slices, self-administration and conditioned place preference tests to investigate the rewarding potential of pregabalin and naloxone-precipitated morphine withdrawal to evaluate opioid withdrawal symptoms. Further, we ran a pilot single-blind, randomized, controlled trial (34 heroin addicts) to evaluate the efficacy and safety of pregabalin in the treatment of opioid withdrawal syndrome. Pregabalin alone did not induce glutamate receptor neuroplasticity of dopamine neurons in the ventral tegmental area, but pre-treatment with pregabalin suppressed morphine-induced neuroplasticity, hyperlocomotion and morphine self-administration. Pregabalin administration after chronic morphine exposure failed to induce any rewarding effects. Instead, pregabalin suppressed withdrawal symptoms in both morphine-treated mice and opioid addicts and was well tolerated. Intriguingly, pregabalin administration after a low dose of morphine strongly facilitated ventral tegmental area neuroplasticity and led to increased conditioned place preference. Pregabalin appears to have the efficacy to counteract both reinforcing and withdrawal effects of opioids, but it also has a potentiating effect when given to mice with existing opioid levels.
加巴喷丁类似物普瑞巴林是一种快速作用的抗焦虑药和镇痛药，在监督下戒断阿片类药物可能是合适的。然而，由于其未知的成瘾风险以及阿片类药物滥用者自行服用普瑞巴林后死亡率上升，临床医生一直对此持谨慎态度。在这里，我们研究了普瑞巴林和吗啡对小鼠多巴胺系统奖赏功能的相互作用，以及普瑞巴林对阿片类药物成瘾者戒断的疗效。在给小鼠用普瑞巴林和吗啡治疗后，我们用电生理学研究中脑切片中的神经可塑性，用自我给药和条件性位置偏爱测试研究普瑞巴林的奖赏潜力，以及纳洛酮诱发的吗啡戒断对评价阿片类药物戒断症状的影响。此外，我们进行了一项单盲、随机、对照试验的初步研究（34 名海洛因成瘾者），以评估普瑞巴林治疗阿片类药物戒断综合征的疗效和安全性。普瑞巴林单独使用不会诱导腹侧被盖区多巴胺神经元的谷氨酸受体神经可塑性，但预先给予普瑞巴林可抑制吗啡诱导的神经可塑性、过度活跃和吗啡自我给药。慢性吗啡暴露后给予普瑞巴林不会产生任何奖赏作用。相反，普瑞巴林抑制了吗啡治疗的小鼠和阿片类药物成瘾者的戒断症状，且耐受性良好。有趣的是，在给予低剂量吗啡后给予普瑞巴林会强烈促进腹侧被盖区的神经可塑性，并导致条件性位置偏好增加。普瑞巴林似乎具有对抗阿片类药物的强化和戒断作用的疗效，但在给予已经存在阿片类药物水平的小鼠时，它也具有增强作用。
