a Iranian National Center for Addiction Studies , Tehran University of Medical Sciences , Tehran , Iran.
b Department of Neuroscience, School of Advanced Technologies in Medicine , Tehran University of Medical Sciences , Tehran , Iran.
Am J Drug Alcohol Abuse. 2019;45(1):84-89. doi: 10.1080/00952990.2018.1529182. Epub 2019 Jan 11.
Besides the analgesic effect of tramadol, prolonged exposure to tramadol can induce adaptive changes thereby leading to dependence and tolerance. Tramadol induces its effect via µ-opioid receptor (MOR). However, tramadol has other targets such as serotonin and epinephrine transporters.
CREB and ΔFosB are transcriptional factors, which are involved in the behavioral abnormalities underlying drug abuse. In this study, the effects of acute and chronic tramadol treatments on MOR, ΔFosB, and CREB levels were studied.
For this purpose, 36 male Wistar rats were used. The animals were divided into two main groups. A total of 18 animals received tramadol (0, 5, and 10 mg/kg) acutely and 18 animals received the same doses for the following 14 days. One hour after the last injection, the NAC and PFC were dissected and kept at -80°C in liquid nitrogen. Using western blotting technique, the levels of MOR, ΔFosB, and p-CREB were evaluated.
In the NAC, acute tramadol exposure increases the levels of MOR and p-CREB. Moreover, chronic tramadol administration in this region results in elevated levels of MOR, ΔFosB and p-CREB compared with saline-treated rats. The levels of MOR and p-CREB in the PFC increased in both acute and chronic tramadol exposure. Also, ΔFosB levels increased only following chronic tramadol administration. The results revealed that adaptive changes occurred during drug exposure.
We concluded that both CREB and ΔFosB played a role in tramadol dependence. Additionally, increased MOR levels during tramadol treatments might be due to receptor desensitization.
除了曲马多的镇痛作用外，长期暴露于曲马多会导致适应性变化，从而导致依赖和耐受。曲马多通过μ-阿片受体（MOR）发挥作用。然而，曲马多还有其他靶点，如 5-羟色胺和去甲肾上腺素转运体。
CREB 和 ΔFosB 是转录因子，它们参与药物滥用引起的行为异常。在这项研究中，研究了急性和慢性曲马多治疗对 MOR、ΔFosB 和 CREB 水平的影响。
为此，使用了 36 只雄性 Wistar 大鼠。动物分为两组。共有 18 只动物接受了曲马多（0、5 和 10mg/kg）的急性治疗，另外 18 只动物接受了相同剂量的治疗 14 天。最后一次注射后 1 小时，解剖 NAC 和 PFC 并在液氮中-80°C 保存。使用 Western blot 技术评估 MOR、ΔFosB 和 p-CREB 的水平。
在 NAC 中，急性曲马多暴露会增加 MOR 和 p-CREB 的水平。此外，与生理盐水处理的大鼠相比，该区域的慢性曲马多给药导致 MOR、ΔFosB 和 p-CREB 水平升高。在急性和慢性曲马多暴露下，PFC 中的 MOR 和 p-CREB 水平均升高。此外，只有在慢性曲马多给药后 ΔFosB 水平才增加。结果表明，在药物暴露期间发生了适应性变化。
我们得出结论，CREB 和 ΔFosB 都在曲马多依赖中发挥作用。此外，曲马多治疗期间 MOR 水平的增加可能是由于受体脱敏。
