Study On The Relationship Between Dexmetomidine And Fentanyl-Induced Hyperalgesia

Objective:This study observed the effect on opioid induced hyperalgesia(Opioid induced hyperalgesia,OIH)by pre-injection of dexmetomidine into fentanyl-induced acute hyperalgesia in rats.In order to observe the expression of glial fibrillary acidic protein(Glial fibrillary acidic protein,GFAP)and microglial marker(Ionized calcium binding adaptor molecule 1(iBa-1)in spinal dorsal horn of OIH group(model group)and other groups,The expression ofα2A adrenergic receptor,iNOS and substance P in each group was observed,so that it could provide some help for the prevention and treatment of OIH.Methods:1.Establishment of OIH model and measurement of mechanical pain threshold and thermal pain threshold of rats in each group:30 SD rats(n=6)of 280~320g male SPF grade were randomly divided into 5 groups:saline group(NS group):subcutaneous injection of saline,5 times;1ml,fentanyl group(model group,group F):subcutaneous injection of saline once,1ml,fentanyl 4 times,Three dose groups(12.5μg/Kg,25μg/Kg,50μg/Kg)dexmetomidine and fentanyl mixture(experimental group,Dex+F group)Dex1+F,Dex2+F,Dex3+F):dexmetomidine(12.5μg/Kg,25μg/Kg,50μg/Kg)×once was given subcutaneously,followed by fentanyl 60μg/Kg×4 times,with an interval of 15minutes.Mechanical pain threshold(Tail flick threshold,TFT)and thermal pain threshold(Paw withdrawal latency,PWL)were measured and compared at 30 minutes before administration(T0),2 hours after administration(T1),3 hours(T2),4 hours(T3)and 1~5days after administration(T4-T8).TFT)and thermal pain threshold(Paw withdrawal latency,PWL).2.The expression ofα2_A-AR,astrocyte marker GFAP,microglia marker iBa-1,iNOS and substance P in each group were measured and analyzed.The lumbar enlargement of spinal cord was taken one day after administration.Eight rats in each group were randomly selected to measure the changes ofα2_A-AR and iNOS(Western blot),four rats were used to determine the expression of substance P(enzyme-linked immunosorbent assay,Elisa),eight rats were used to observe astrocyte markers GFAP and microglial markersy iBa-1(immunofluorescence).Results:1.The results of pain threshold showed that the mechanical pain threshold TFT and thermal pain threshold PWL in group F and Dex+F were higher than those in NS group at2~4 h,while those in group F and Dex1+F were lower than those in NS group at 1~3days,most significantly on first day.The level of NS returned to the level of NS on the 4th day,and there was no significant difference between Dex2+F and Dex3+F group and NS group on the first and 5th day.2.The results of Western blot showed that the expression ofα2_A-AR decreased and the expression of iNOS increased in group F and Dex1+F compared with NS group,and the expression ofα2_A-AR increased and iNOS expression decreased in Dex2+F and Dex3+F groups compared with group F;The results of substance P determined by enzyme-linked immunosorbent assay(Elisa)showed that compared with group F,the expression of substance P in Dex+F group decreased,and the number of GFAP and iBa-1 positive cells in group F was higher than that in NS and Dex+F groups.Conclusion:1.Dexmetomidine can prevent and treat OIH induced by fentanyl.2.The prevention and treatment of OIH with dexmetomidine is closely related to the inhibition of astrocyte and microglia activation,the increase ofα2_A-AR expression and the decrease of iNOS and substance P expression.