Tramadol induces changes in Δ-FosB, μ-opioid receptor, and p-CREB level in the nucleus accumbens and prefrontal cortex of male Wistar rat

Background: 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 mu-opioid receptor (MOR). However, tramadol has other targets such as serotonin and epinephrine transporters. Objective: CREB and Delta FosB 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, Delta FosB, and CREB levels were studied. Methods: 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 degrees C in liquid nitrogen. Using western blotting technique, the levels of MOR, Delta FosB, and p-CREB were evaluated. Results: 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, Delta FosB 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, Delta FosB levels increased only following chronic tramadol administration. The results revealed that adaptive changes occurred during drug exposure. Conclusion: We concluded that both CREB and Delta FosB played a role in tramadol dependence. Additionally, increased MOR levels during tramadol treatments might be due to receptor desensitization.