Relationship of dose to morphine tolerance in the chick embryo

Morphine tolerance and dependence can be produced in chick embryos by injecting 20 mg/kg into the airspace of the egg daily for 4 days beginning on incubation day 12. The experiments in this report examined the production of tolerance with lower doses of morphine (2.5, 5.0 and 10.0 mg/kg). Treatment of embryos for 4 days did not produce tolerance on day 16 when the challenge dose was the same as the dose used for pretreatment and when activity was recorded at only one time after injection. Further studies measuring activity at multiple time-points and/or utilizing a lower challenge dose indicated that tolerance was present. Studies of activity after 4 or 8 days of pretreatment revealed a dose-effect relationship. Pretreatment with 2.5 mg/kg produced a lesser degree of tolerance than that produced by the higher pretreatment doses. These embryos were tolerant on day 16 after four injections but not on day 19 after eight injections, due perhaps to more rapid metabolism of morphine with age. There were no differences between the responses of the 5.0 and 10.0 mg/kg groups to morphine challenge. While both of these doses produced tolerance to a low challenge dose of morphine by day 16, pretreatment at doses higher than 10.0 mg/kg was necessary for production of tolerance to high doses.