The Role Of AQP4 Inhibitor In Remifentanil Induced Hyperalgesia

Objective: The aim of this study was to demonstrate AQP4 inhibitor's function and mechanism in remifentanil induced postoperative hyperalgesia,via observing the changes of mice's pain behavior parameters at four time points(-1d,1d,2d,7d).,as well as detecting the change of AQP4 and TRPV4 expression in mice's lumbar spine cord through remifentanil infusion and postoperative pain modeling.Methods: 64 healthy male CD1 mice were randomized into four groups,nature saline infusion without plantar incision group(group C),remifentanil infusion with plantar incision group(group R+1),remifentanil and AQP4 inhibitor(TGN020)infusion with plantar incision group(group R+I+AQP4 inhibitor),remifentanil and menstruum infusion with plantar incision group(group menstruum),respectively.Besides,mechanical and thermal pain threshold were measured at-1d,1d,2d and 7d after surgery.Further,Western Blot and RT-q PCR were applied to detect the expression of AQP4 and TRPV4 in spinal cord(L4-L6 segments)at those four time points.Results: There was no difference of basic thermal and mechanical pain threshold in four groups.Compared with measurement of the LPWTL and L50%MWT at one day before modeling,the LPWTL and L50%MWT of group R+I and group R+I+AQP4 inhibitor were significantly decreased(p<0.05),particularly at the first and second day after modeling.Likewise,in terms of the LPWTL and L50%MWT,the pain threshold of group C and group R+I+AQP4 inhibitor were lower than that of group R+I and group menstruum.Taking the counterpart of right hindpaw skin into account,namely RPWTL and R50%MWT,in comparison with the pain threshold parameter of the day before modeling,the RPWTL and R50%MWT in both group R+I and group menstruum were remarkably decreased,while no difference was found in other two groups.Apart from this,from the modeling onwards,the RPWTL and R50%MWT of group R+I and group menstruum were lower than those of group R+I+AQP4 inhibitor.According to Western Blotting,the expression of AQP4,except the AQP4 inhibitor group,was the highest at 48 hours after modeling,and kept that relatively high level until the seventh day.Precisely,at the second day,AQP4 expression level of group R+I,as well as group menstruum,was higher than group C's.However,we did not observe the AQP4 expression's up-regulation trend in AQP4 inhibitor group by Western Blotting and RT-q PCR.Conclusion: Clinical dosage of remifentanil was likely to decrease the postoperative mechanical and thermal pain threshold in mice,namely hyperalgesia which was most remarkable at 24 h and 48 h after surgery.The thermal pain threshold of the group with AQP4 inhibitor was obviously higher than the one without inhibitor.Apart from this,the up-regulation of AQP4 expression was detected in the lumbar spinal cord after injection of remifentanil.Meanwhile,the similar physiological change,the up regulating expression of TRPV4,was found in the mice model.Above all,the integral results indicate that both AQP4 and TRPV4 might play a role in the mechanism of remifentanil induced hyperalgesia.Furthermore,AQP4 inhibitor administration is possible to interfere with the hyperalgesia process.