Extracellular signal-regulated kinase (ERK) inhibition does not prevent the development or expression of tolerance to and dependence on morphine in the mouse

The clinical use of opioids is limited by the development of tolerance and physical dependence. Opioid tolerance and dependence are believed to result from complex adaptations in the CNS, representing a form of neural plasticity. Extracellular signal-regulated kinases (ERKs) are involved in many forms of neural plasticity, and therefore could also be involved in the development of opioid tolerance and dependence. In this study, we investigated the effect of a systemically bioavailable MEK (ERK kinase) inhibitor, SL327, upon the development and the expression of tolerance to and dependence on morphine in mice. In tolerance and dependence development studies, two strains of mice were treated daily for 8 or 9 days with 5mg/kg morphine s.c. Tolerance development was assessed by tail flick latency. Withdrawal was then precipitated by subcutaneous injection of 2mg/kg naloxone s.c. and signs recorded. Co-administration of 50mg/kg SL327 i.p. prior to morphine administration had no effect on the development of tolerance or withdrawal signs. To study possible effects of ERK inhibition on the expression of tolerance and dependence, mice were implanted with 75mg morphine pellets s.c. Tolerance and dependence were assessed as previously described. An acute i.p. injection of 50mg/kg SL327 after 4 days of morphine exposure had no effect on the expression of either morphine tolerance or physical dependence. To verify that this dose of SL327 inhibited morphine-induced ERK modulation, mice received an acute i.p. injection of 50mg/kg SL327 prior to morphine administration, and sacrificed 30min later. Western blots demonstrated that SL327 did inhibit morphine-induced ERK modulation. Taken together, these data suggest that unlike many other observed forms of neural plasticity, the ERK signaling cascade is not involved in the development or expression of opioid tolerance and dependence.