Evidence of a long-term rhythm in withdrawal, brain concentration, and hepatic clearance of morphine in the rat.

Abstract

The technique of morphine pellet implantation was utilized to produce physical dependence on morphine in both male and female rats. At the peak of dependence (96 h), naloxone hydrochloride (1.0 mg/kg s.c.) was administered to precipitate withdrawal and the mean number of ‘wet dog’ shakes was determined for 30 min. A predictable and rhythmic cycle of approximately 6 weeks was observed in the number of ‘wet dog’ shakes in morphine-withdrawn animals. This rhythm was not a sex-related phenomenon; there was no discernable rhythm in total body weight loss during the withdrawal period. The intensity of the withdrawal response was inversely related to the brain concentration of morphine. However, the periodicity of the long-term rhythm in ‘wet dog’ shakes was not similar to that of brain concentrations of morphine. An 8 month study of the <i>in vitro</i> hepatic clearance of morphine in the nondependent rat indicated that there are long-term fluctuations in the rate at which morphine is cleared from the rat liver. Also, development of dependence on morphine in the rat was not found to consistently alter the hepatic clearance of the drug. These findings suggest more than one controlling mechanism in the fluctuation of ‘wet dog’ shakes and that the time of the year at which the study is conducted is an important variable in the determination of the effects of morphine dependence in the rat.