Pang Gang, Wu Xian, Tao Xinrong, Mao Ruoying, Liu Xueke, Zhang Yong-Mei, Li Guangwu, Stackman Robert W, Dong Liuyi, Zhang Gongliang
College of Basic Medical Sciences, Anhui Medical University Hefei, China.
College of Medicine, Anhui University of Science and Technology Huainan, China.
Front Pharmacol. 2016 Dec 26;7:514. doi: 10.3389/fphar.2016.00514. eCollection 2016.
The increasing prescription of opioids is fueling an epidemic of addiction and overdose deaths. Morphine is a highly addictive drug characterized by a high relapse rate - even after a long period of abstinence. Serotonin (5-HT) neurotransmission participates in the development of morphine dependence, as well as the expression of morphine withdrawal. In this study, we examined the effect of blockade of 5-HT receptors (5-HTRs) on morphine-induced behavioral sensitization and withdrawal in male mice. 5-HTR antagonist MDL 11,939 (0.5 mg/kg, i.p.) suppressed acute morphine (5.0 mg/kg, s.c.)-induced increase in locomotor activity. Mice received morphine (10 mg/kg, s.c.) twice a day for 3 days and then drug treatment was suspended for 5 days. On day 9, a challenge dose of morphine (10 mg/kg) was administered to induce the expression of behavioral sensitization. MDL 11,939 (0.5 mg/kg, i.p.) pretreatment suppressed the expression of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. MDL 11,939 (0.5 mg/kg, i.p.) prevented naloxone-precipitated withdrawal in morphine-dependent mice on day 7. Moreover, chronic morphine treatment increased 5-HTR protein level and decreased the phosphorylation of extracellular signal-regulated kinases in the prefrontal cortex. Together, these results by the first time demonstrate that 5-HTRs modulate opioid dependence and blockade of 5-HTR may represent a novel strategy for the treatment of morphine use disorders.
(i)Blockade of 5-HT receptors suppresses the expression of morphine-induced behavioral sensitization.(ii)Blockade of 5-HT receptors suppresses naloxone-precipitated withdrawal in morphine-treated mice.(iii)Chronic morphine exposure induces an increase in 5-HT receptor protein level and a decrease in ERK protein phosphorylation in prefrontal cortex.
阿片类药物处方的增加正助长成瘾和过量死亡的流行。吗啡是一种极易成瘾的药物，其特征是复发率高——即使经过长时间的戒断。血清素（5-羟色胺，5-HT）神经传递参与吗啡依赖的发展以及吗啡戒断的表现。在本研究中，我们研究了5-HT受体（5-HTRs）阻断对雄性小鼠吗啡诱导的行为敏化和戒断的影响。5-HTR拮抗剂MDL 11,939（0.5毫克/千克，腹腔注射）抑制急性吗啡（5.0毫克/千克，皮下注射）诱导的运动活动增加。小鼠每天接受两次吗啡（10毫克/千克，皮下注射），共3天，然后停药5天。在第9天，给予一剂激发剂量的吗啡（10毫克/千克）以诱导行为敏化的表现。MDL 11,939（0.5毫克/千克，腹腔注射）预处理抑制了吗啡诱导的行为敏化的表现。另一组小鼠在7天内接受递增剂量的吗啡以诱导吗啡依赖。MDL 11,939（0.5毫克/千克，腹腔注射）在第7天预防了吗啡依赖小鼠中纳洛酮诱发的戒断。此外，慢性吗啡治疗增加了5-HTR蛋白水平，并降低了前额叶皮质中细胞外信号调节激酶的磷酸化。总之，这些结果首次证明5-HTRs调节阿片类药物依赖，阻断5-HTR可能代表一种治疗吗啡使用障碍的新策略。
（i）阻断5-HT受体抑制吗啡诱导的行为敏化的表现。（ii）阻断5-HT受体抑制吗啡处理小鼠中纳洛酮诱发的戒断。（iii）慢性吗啡暴露诱导前额叶皮质中5-HT受体蛋白水平增加和ERK蛋白磷酸化减少。
