Pharmacokinetics of morphine related to the regulation of gonadal and thyroidal functions in pubertal and adult male cynomolgus monkeys

Abstract

The purposes of this this study are 1) to investigate the acute effect of morphine hydrochloride on serum prolactin (PRL), thyrotropin (TSH), thvroxin (T₄), testosterone (T) and cortisol (C) levels in pubertal male cynomolgus monkeys comparing to adult male monkeys and 2) to follow the alterations of T, E₂, PRL, T₄ , TSH and C related to pharmacokinetics of morphine hydrochloride during long-term treatment and drug withdrawal periods including some physiological changes. Monkeys were divided into 3 groups 1) pubertal group injected with 3.0 mg/kg/day for 74 days 2) adult group with was subdivided into 3 groups injected with 1.5, 3.0 and 6.0 mg/kg/day morphine for 130, 74 and 110 days, respectively and 3) control group injected with 0.5 ml saline for 149-170 days. Acute effect of subcutaneous injection of morphine at the dose 3.0 mg/kg to 3 pubertal monkeys and 1.5, 3.0 and 6.0 mg/kg to 4, 3 and 3 adult monkeys, respectively showed that PRL began to increase at 15 min and peaked at 30 min, whereas T and C declined to a nadir at 6.5-10 h and 2.5 h, respectively. The decreased or increased levels of these hormones related to the dose of morphine injected. However, serum TSH and T₄ levels determination follow up to 10 h did not show any change. A circadian pattern of some hormones was observed. Long-term daily morphine injection of which each blocd sample was taken 20 h after injection did not show any prominent changes of hormonal levels in any monkey groups and the alteratior of turnover rate was distinctive in each group. Monkey injected with 1.5 and 3.0 mg/kg/day morphine exhibited a decrease in turnover rate values while in dose 6.0 mg/kg/day injection was negligible any effect. It means that monkeys can adjust themselves to the effect and disposition of drug after daily morphine administration (pharmacological and dispositional). Cortisol, a prerequisite hormone for stress levels, showed a marked increase during the drug withdrawal symptoms in all monkeys. This sudden increase of cortisol levels could influence on T₄, E₂ and testosterone levels and these alterations could recover within 1 month. Transient hyperprolactinemia happened every day from each morphine injection could also induce galactorrhea symptom when it was synchronous with the markedly decrease in testosterone levels in male cynomolgus monkeys particularly in susceptible monkeys whom displayed the high basal PRL levels. The colour of excretion was principally depend upon the level of PRL. If it inferred to the effect of morphine to induce PRL elevation, milk excretion, anorexia, and decrease in testosterone levels, testicular size and body weight, these effects may cause an infertility in male cynomolgus monkeys. However, these effects could return to normal after the drug withdrawal and its latency depended upon the dose of morphine injection.