Effects Of Fentanyl On Chronic Morphine Tolerance In Periaqueductal Gray And Locus Ceruleus Of Rats

Object The purpose of this study was to evaluate the expression of mureceptor, delta-receptor,β-arrestin1 andβ-arrestin2 in periaqueductal gray and locus ceruleus of rats tolerant to morphine.Meanwhile,to examine whether chronic morphine tolerance can be alleviated by fentanyl.Methods Sixty-four healthy male Sprague-Dawley rats weighing 230±20g were randomly divided into eight groups of eight rats each:group NS,group M,group F₁,group F₂,group F₃,group MF₁,group MF₂,group MF₃.Rats in group NS received only subcutaneous normal saline 1ml·kg^-1.Rats in group M received subcutaneous morphine 10ml·kg^-1 followed by NS 1ml·kg^-1.In group F₁,F₂, F₃,fentanyl 3,6,12μg·kg^-1 were respectively injected followed by normal saline 1ml·kg^-1 In group MF₁,group MF₂,group MF₃,morphine 10ml·kg^-1 was injected subcutaneously followed by fentanyl 3,6,12μg·kg^-1 respectively.All rats received drugs or normal saline administration twice a day for nine days consecutively.The hot radiation tail flick test was performed to monitor Tail Flick Latency after injection every morning.Tail Flick Latency was measured three times and then the values were calculated to give an average to be the value of pain threshold.All animals were killed on the ninth day after measurement of pain threshold.Periaqueductal grays and locus ceruleus of rats were removed for determination of the expression of mu-receptor,delta-receptor,β-arrestin1 andβ-arrestin2 by RT-PCR and Western Blot.Results Compared with group NS,TFL of the group M was significantly increased after first morphine injection(P＜0.01).But TFL of the group M returned to the baseline value following chronic morphine treatment. Compared with group M,TFL was increased in group MF₂ and MF₃ at the seventh day and the ninth day(P＜0.05 or 0.01),however,TFL of group MF₁ was negative(P＞0.05). The expression of mu-receptor mRNA and protein was significantly lower in group M than in group NS(P＜0.01).Compared with group M,the expression of mu-receptor mRNA and protein was significantly increased in group MF₂ and MF₃(P＜0.05 or 0.01) but there was no significant change in group MF₁(P＞0.05).The expression ofβ-arrestin1 andβ-arrestin 2 mRNA and protein was significantly decreased in group M as compared with group NS(P＜0.01).Compared with group M,the expression ofβ-arrestin1 andβ-arrestin2 mRNA and protein was significantly increased in group MF₂ and MF₃(P＜0.05 or 0.01),but there was no significant change in group MF₁(P＞0.05).Conclusion Fentayl 6 and 12μg·kg^-1can partly inhibit morphine tolerance through increasing of the expression of mu-receptor,β-arrestin1 andβ-arrestin 2 in periaqueductal gray and locus ceruleus of rats tolerant to morphine.