Tramadol induces changes in Δ-FosB, µ-opioid receptor, and p-CREB level in the nucleus accumbens and prefrontal cortex of male Wistar rat (2019)

Am J Drug Alcohol Abuse. 2019;45(1):84-89. doi: 10.1080/00952990.2018.1529182.

Sadat-Shirazi MS1,2, Babhadi-Ashar N1, Khalifeh S3, Mahboubi S2, Ahmadian-Moghaddam H1, Zarrindast MR1,4,5.



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.

KEYWORDS: CREB; Tramadol; nucleus accumbens; prefrontal cortex; µ-opioid receptor; ΔFosB

PMID: 30632799

DOI: 10.1080/00952990.2018.1529182