Further studies on the alteration of analgesic receptor-antagonist interaction induced by morphine.

In previous studies, we observed that pretreatment of mice with narcotic analgesics induced a substantial increase in the efficacy of narcotic antagonists whereas pretreatment with non-narcotic drugs or antagonists did not. In the present study, experiments were designed to see whether or not there was a relationship between the development of narcotic tolerance and the induction of increased narcotic antagonism. The increase in the efficacy of naloxone due to treatment of animals with morphine is observed before analgesic tolerance can be detected and the efficacy of the antagonist rises much faster than the development of tolerance. The increased efficacy of naloxone reaches a maximum in highly tolerant animals, i.e., those that received a morphine pellet implant for 3 days. In the tolerant state, the apparent pA 2 value of morphine-naloxone was 7.82 compared with 6.90 in control animals. This represented a greater than 8-fold increase in the apparent affinity constant of the analgesic receptors for the antagonist and indicated that a qualitative rather than a quantitative change in receptors took place with the development of narcotic tolerance. Acute injections of cycloheximide did not alter the ED5O of morphine or the increased potency of naloxone. However, daily injections of cycloheximide for 7 days (4 days prior to morphine pellet implantation and 3 days during the implant) inhibited the development of tolerance by 84% and the increased efficacy of naloxone by 64%. The increased efficacy of naloxone due to treatment with morphine appears to be a sensitive indicator of the development of tolerance.