The role of extracellular signal-regulated kinase signal pathway in the development of chronic morphine tolerance in rats

Abstract

Objective To investigate the role of extracellular signal-regulated kinase(ERK)signal pathway in the spinal cord in the development of chronic morphine tolerance.Methods Thirty healthy male SD rats weighing 300-350 g in which intrathecal(IT)catheters were successfully implanted without complication were randomly divided into 3 groups(n = 10 each): group Ⅰ control(group C);group Ⅱ morphine tolerance(group M)and group Ⅲ morphine tolerance + PD98059(ERK upstream kinase MEK inhibitor)(group P).Morphine tolerance was induced with IT morphine 10 μg twice a day for 7 consecutive days.In group P PD98059 10 μg was injected IT at 30 min before each morphine administration.Tail flick latency(TFL)(the time between the onset of heat stimulus and voluntary tail withdrawal)was measured once a day at 30 min after first IT morphine administration and at 1 day after last IT morphine.Maximum analgesic effect(MPE)was calculated.MPE =(TFL after IT morphine - baseline TFL)/(12 - baseline TFL)× 100%.The animals were sacrificed after last TFL measurement.The L3-5 segment of the spinal cord was isolated for determination of the expression of μ-receptor and phosphorylated ERK 1/2(p-ERK1/2)by Western blot analysis and fluoroimmunoassay.Results Morphine tolerance was induced in group M and M + P.MPE was higher in group P than in group M.The expression of μ-receptor in spinal dorsal horn was significantly lower while the p-ERK1/2 expression was higher in group M than in group C.IT PD98059 significantly up-regulated μ-receptor expression and down-regulated p-ERK expression in group P as compared with group M.Conclusion ERK signal pathway is involved in the development of chronic morphine tolerance in rats. Key words: Morphine; Drug tolerance; Extracellular signal-regulated kinase