Integrative Life Sciences Doctoral Program, Virginia Commonwealth University, 1000 West Cary St., Richmond, VA, 23284, USA.
Department of Forensic Science, Virginia Commonwealth University, 1015 Floyd Avenue, Richmond, VA, 23284, USA.
Psychopharmacology (Berl). 2022 Jul;239(7):2187-2199. doi: 10.1007/s00213-022-06093-w. Epub 2022 Feb 24.
Tianeptine is a mu-opioid receptor (MOR) agonist with increasing reports of abuse in human populations. Preclinical data regarding the abuse potential and other opioid-like adverse effects of tianeptine at supratherapeutic doses are sparse.
The present study evaluated tianeptine in a rat model of abuse potential assessment and in mouse models of motor, gastrointestinal, and respiratory adverse effects.
Abuse potential was assessed in adult male Sprague-Dawley rats using an intracranial self-stimulation (ICSS) procedure to determine effects of acute and repeated tianeptine on responding for electrical brain stimulation. Male ICR mice were used to determine the effects of tianeptine in assays of locomotor behavior and gastrointestinal motility. Male Swiss-Webster mice were monitored for respiratory changes using whole-body plethysmography.
In rats, acute tianeptine produced weak and delayed evidence for abuse-related ICSS facilitation at an intermediate dose (10 mg/kg, IP) and pronounced, naltrexone-preventable ICSS depression at a higher dose (32 mg/kg, IP). Repeated 7-day tianeptine (10 and 32 mg/kg/day, IP) produced no increase in abuse-related ICSS facilitation, only modest tolerance to ICSS depression, and no evidence of physical dependence. In mice, tianeptine produced dose-dependent, naltrexone-preventable locomotor activation. Tianeptine (100 mg/kg, SC) also significantly inhibited gastrointestinal motility and produced naloxone-reversible respiratory depression.
Tianeptine presents as a MOR agonist with resistance to tolerance and dependence in our ICSS assay in rats, and it has lower abuse potential by this metric than many commonly abused opioids. Nonetheless, tianeptine produces MOR agonist-like acute adverse effects that include motor impairment, constipation, and respiratory depression.
天普汀是一种μ-阿片受体（MOR）激动剂，在人类群体中滥用的报告越来越多。关于天普汀在治疗剂量以上的滥用潜力和其他类阿片样不良反应的临床前数据很少。
本研究在大鼠滥用潜力评估模型和小鼠运动、胃肠道和呼吸不良反应模型中评估了天普汀。
通过颅内自我刺激（ICSS）程序评估成年雄性 Sprague-Dawley 大鼠的滥用潜力，以确定急性和重复天普汀对电脑刺激反应的影响。雄性 ICR 小鼠用于确定天普汀在运动行为和胃肠道动力测定中的作用。使用全身 plethysmography 监测雄性瑞士-Webster 小鼠的呼吸变化。
在大鼠中，天普汀在中等剂量（10mg/kg，IP）下产生了微弱和延迟的与滥用相关的 ICSS 促进作用的证据，在较高剂量（32mg/kg，IP）下产生了明显的、纳洛酮可预防的 ICSS 抑制作用。重复 7 天的天普汀（10 和 32mg/kg/天，IP）没有增加与滥用相关的 ICSS 促进作用，只有对 ICSS 抑制作用的适度耐受，没有身体依赖的证据。在小鼠中，天普汀产生剂量依赖性、纳洛酮可预防的运动激活。天普汀（100mg/kg，SC）还显著抑制了胃肠道动力，并产生了纳洛酮可逆转的呼吸抑制。
天普汀作为一种 MOR 激动剂，在我们的大鼠 ICSS 测定中表现出对耐受和依赖的抵抗力，根据这一指标，它的滥用潜力低于许多常用的阿片类药物。尽管如此，天普汀还是产生了 MOR 激动剂样的急性不良反应，包括运动障碍、便秘和呼吸抑制。
