Influence Of Low-dose Naloxone On The Development Of Morphine Tolerance In Rats

ObjectiveMorphine is an opioid analgesic commonly used in clinic. But its tolerance and side effects have limited its use to a great extent. The researches in our department have shown that low-dose of mu opioid receptor antagonist like naloxone when administered together with morphine can decrease its side effects such as nausea and vomiting without affecting its analgesic effect. It is thought to be attributed to the bimodal modification of the mu opioid receptor.Morphine tolerance is defined as decreased analgesic effect or larger dose required to obtain the same effect of analgesia after repeated administration, resulting in the shift of the dose-effect curve to the right. With the appearance of tolerance, the dose has to be increased over and again and together with higher possibility of side effects, which becomes a clinical problem for the doctors difficult to deal with.So this experiment was designed to observe the effect of low-dose naloxone on the development of morphine tolerance in rats.Methods20 male Wistar rats were included in this experiment and rats with tail abnormities were ruled out. The rats were distributed into 2 groups randomly, with 10 rats in each group. The rats were administered with either morphine 10mg/kg or morphine 10mg/kg and naloxone 10ng/kg subcutaneously for consecutive 7 days. TFL were measured before drug administration as basal value and measured again 30 minutes after 1st, 3rd, 6th, 9th, 12th, 15th drug administration respectively.After the last drug use and TFL measuring, the rats were killed by decapitation. Brain tissue including PAG was excised and put into 10% formalin. The tissue was inspected for PKA staining by method of immunohistochemical analysis. The results were analyzed by SPSS 13.0 software. Comparison of general data and grey scale was performed by methods of independent t test, and comparison between groups was performed by methods of paired t test. Measurement data was expressed by mean value±standard deviation and p<0.05 is believed that the difference is statistically significant.Results2 rats died and another 1 rat got its tail burned and they were all excluded out of the experiment.At the beginning, TFL and MPE% in both groups increased significantly after morphine injection. With the repeated use of morphine, TFL and MPE% in both groups decreased. But they decreased more rapidly in M group compared with that of MN group (P<0.05).The PKA staining in the M group was deeper than that in MN group (p<0.05).ConclusionLow-dose naloxone delayed the development of morphine tolerance in rats.