Abstract

The development of morphine tolerance and naloxone-precipitated withdrawal was studied in intact cats and correlated with neocortical acetylcholine (ACh) release in midpontine pretrigeminal transected preparations. Cats were given morphine sulfate s.c. every 8 hours for 15 days. The dosage (calculated as base) was increased gradually from 9 to 30 mg/kg/day. On gross behavioral observation surviving cats showed obvious tolerance to morphine toward the end of the treatment period. Naloxone, 1.0 mg/kg i.v., induced a withdrawal syndrome characterized by predominant central nervous system depression, vomiting and stupor in five intact cats. The remaining animals were subjected to a midpontine pretrigeminal brainstem transection under halothane-air anesthesia. Subsequently, the neocortical release of ACh after i.v. morphine and/or naloxone was determined. Morphine-tolerant animals had a shift to the right in their dose-effect curves on arterial blood pressure and on inhibition of neocortical ACh release. Similarly electroencephalogram activation produced by acute morphine was less prolonged in the 15-day morphine-treated animals. Naloxone, 1.0 mg/kg i.v., produced an initial hypertension and electroencephalogram slow waves in the morphine-dependent cats. An initial inhibition of ACh release and a subsequent return to control ACh release levels with a possible enhanced release was observed. The data indicate a far more complex diphasic effect on neocortical ACh release during naloxone-precipitated withdrawal than was initially predicted.