Sex-related differences in antinociception and tolerance development following chronic intravenous infusion of morphine in the rat: Modulatory role of testosterone via morphine clearance

This study investigated possible sex-related differences in levels of antin ociception and the rate of development of tolerance to the antinociceptive effects following prolonged (48 h) intravenous (i.v.) morphine administrati on in the rat. Groups of adult intact male, castrated male, female, and tes tosterone-pretreated female Sprague-Dawley rats received prolonged (48 h) i nfusions of i.v. morphine (5 or 10 mg/day) plus intra-arterial (i.a.) salin e or i.v. morphine (5 mg/day) plus i.a. chloramphenicol (300 mg/day). Antin ociception was quantified using the hotplate test. Serum concentrations of morphine and morphine-3-glucuronide (M3G) were assayed using high performan ce liquid chromatography with electrochemical detection, whereas the serum testosterone concentrations were quantified using an enzyme-linked immunoso rbent assay method. Consistent with our previous findings in intact male ra ts, prolonged coinfusion of chloramphenicol with morphine produced a marked increase in the extent and duration of morphine antinociception in all exp erimental groups. Additionally, female and castrated male rats developed to lerance more slowly than either intact male or testosterone-pretreated fema le rats, when coinfused with parenteral morphine plus chloramphenicol. Howe ver, mean levels of antinociception were not significantly correlated with either the mean serum morphine or M3G concentrations, but were significantl y inversely correlated with the mean values of the M3G/morphine serum molar concentration ratio. Testosterone pretreatment of female rats for 1 week b efore chronic morphine infusion abolished antinociception and markedly redu ced both the serum morphine and M3G concentrations. These latter findings i mply that testosterone modulates antinociception evoked by prolonged morphi ne infusion in rats via a mechanism that appears to involve modulation of m orphine metabolism.