The Decrease In The Anxiolytic Effect of Morphine After Repeated Use of The Drug In Rats is Associated With Inflammatory Cytokine Signaling Pathways In The Prefrontal Cortex

Abstract

We aim to examine anxiety-like behaviors and expression of specific genes complicated in neuroinflammation in the prefrontal cortex (PFC) after repeated use of morphine. A group of male Wistar rats received injections of morphine (10 mg/kg) twice a day for eight days while a control group received saline (1 ml/kg) instead of morphine. On days 1 and 8, anxiety-like behaviors were evaluated using a light/dark box test. On day 8, opioid dependence was confirmed by measuring the behavioral expression of morphine withdrawal precipitated with naloxone. Expression of neuroinflammation genes were also evaluated at mRNA levels in the PFC on day 8. The results revealed that morphine induced anxiolytic-like effects on day 1, which significantly decreased after the repeated injection of the drug on day 8. The results also revealed that repeated morphine injection significantly increased the mRNA level of Il1, Tnfα, and Il6 but decreased Il1r and Tnfr while increased Il6r in the PFC. The gene expression results also revealed a significant decrease in Tlr1 but not in Tlr4 in the PFC of morphine-dependent rats. Although Erk1 expression had no significant alteration but p38 increased and Jnk3 decreased significantly in the PFC in morphine-dependent rats. Creb and Nfkb significantly increased but Fos expression decreased. Let-7c, mir-133b, and mir-365 also significantly increased in the PFC in morphine-dependent rats. We conclude that the alteration in neuroinflammatory pathways at gene expression level in the PFC may party underlie neuroadaptive changes leading to the decrease in anxiolytic effect of morphine in dependent rats.