Effect of Pioglitazone on Morphine Induced Tolerance to the Analgesic Effects with Attitude to Inflammatory/Apoptosis Pathways

Abstract

Long-term exposure to opiates induces tolerance and dependence. Neurobiological mechanisms of these phenomenons are not completely clear. It has been indicated that neuroinflammation and neuronal apoptotic process are in association with the development of morphine tolerance and dependency. In this study we tried to investigate the effect of pioglitazone, peroxisome proliferator activated receptor gamma (PPAR-) agonist, on morphine-induced tolerance and dependence as well as neuroinflammation and apoptosis in rats central nervous system. Methods Different groups of rats received either morphine (ip) and drugs vehicle (po) or morphine and different doses of pioglitazone (po) once per day. For determination of possible role of PPAR-, effects of PPAR- antagonist, GW-9662, were investigated on the pioglitazone effects. Nociception was assessed using a tail flick apparatus. For 9 days, rats received additive doses of morphine to induce dependence. Naloxone was administrated 2h after morphine last dose, and withdrawal symptoms were recorded for 45 min. Spinal and cortical levels of IL-1, IL-6, TNF- and NF-B activity were evaluated by ELISA kit. The anti-apoptotic factors, Bcl-2 and the pro-apoptotic element FADD were evaluated by western blotting. Results Results showed that oral administration of pioglitazone delayed morphine-induced tolerance and attenuated the dependence. Additionally, pioglitazone attenuated the pro-inflammatory cytokines level and NF-B activity in both cerebral cortex and lumbar spinal cord. Western blotting results showed that amount of Bcl-2 was increased in the pioglitazone treated groups compared to the control group in both samples obtained from cerebral cortex and lumbar spinal cord. Moreover, pioglitazone significantly reduced the amounts of FADD in the both areas as compared to the control group. Furthermore, GW-9662 reversed the above mentioned effects of pioglitazone. Conclusion Oral administration of pioglitazone attenuated the morphine induced tolerance and dependence as well as apoptosis and neuroinflammation in the cerebral cortex and lumbar spinal cord of rat.