Changes in the gene expression of inflammatory cytokine receptors but not toll-like receptors in the midbrain are associated with morphine tolerance in rats

Background and Aim: The chronic administration of morphine for pain management results in the development of a gradual tolerance to morphine. The precise underlying mechanism of morphine tolerance remains still unresolved. According to recent reports, the immune cell signaling also contributes to the decreased efficacy of morphine. It has been reported that activated glia facilitates pain transmission and oppose morphine analgesia. Morphine affects glia by binding to the innate immune receptor toll-like receptor ۴ (TLR۴), leading to the release of proinflammatory cytokines such as interlukine-۱ (IL-۱) and interlukine-۶ (IL-۶). Methods: Two experimental male Wistar rats received a regimen of ۸ days treatments of saline (۱ ml/kg) or morphine (۱۰ mg/kg) twice daily. The analgesic tolerance to the repeated injections of morphine was assessed with a hotplate apparatus on day ۸ of the schedule. For gene expression study, each rat was sacrificed, the whole brain was removed, and the midbrain was dissected on day ۸ of the schedule. The gene expressions of TLR۱, TLR۴, IL-۱R, and IL-۶R were examined by using a real-time q-PCR method. A two-way repeated measure ANOVA was used for analyzing the hotplate data. The real time-PCR results were converted to ۲^-ΔΔCT data, and then an independent t-test was used for the pairwise between group comparisons. P<۰.۰۵ was set as a statistically significant level. Results: In this study, we aim to investigate changes in the gene expression of TLR۱, TLR۴, IL-۱R and IL-۶R in the midbrain of morphine-tolerant rats. Conclusion: The results showed that the morphine treatments induced analgesic tolerance to the drug on day ۸ of the treatments (P<۰.۰۰۱). The results of the q-PCR revealed no significant changes in the gene expression of TLR۱ and TLR۴ at mRNA levels but significant decreases in the gene expression of IL-۱R and IL-۶R (P<۰.۰۵) in the midbrain of morphine-tolerant rats compared to the saline control group.

کلیدواژه ها:

Morphine tolerance ، Interlukine-۱ receptor ، Interlukine-۶ receptor ، Inflammation ، Gene expression