Possible role for integrins in development of tolerance to analgesic effect of morphine in rats

Introduction: There is some evidence supporting the reduced activity of integrins following chronic administration of morphine. This reduction might play a role in morphine tolerance development. Manganese binds to the extracellular domain of integrins and makes them to be activated. The effect of integrins activation using manganese on tolerance development to the analgesic effect of morphine was investigated in this study. Methods: To induce tolerance to analgesic effect of morphine, morphine (15 μg/rat) was injected intrathecally (i.t.) to male adult Wistar rats twice a day for five days. To investigate the effect of manganese, it was injected (20 nmol/rat-i.t.) 15 minutes prior to morphine injections during mentioned period. The analgesic effect of morphine (15 μg/rat) was measured using tail flick test on day 6. Results: The results indicated that in animals which received both manganese and morphine during first 5 days, morphine induced a significant analgesia on day 6. Chronic administration of manganese did not change the pain threshold and morphine induced analgesia. Comparison of morphine analgesia following a single dose of morphine (15 μg/rat) or chronic manganese+morphine, indicated that manganese did not have any effect on the morphine analgesia. Conclusion: Our results showed that, manganese administration prior to morphine is able to prevent morphine tolerance development. It seems that decreased activity of integrins following chronic administration of morphine plays a pivotal role in tolerance development to morphine analgesia. Further investigation needs to determine whether manganese effect is dependent on the integrins role in cell adhesions, or on their intracellular signaling pathways.