Abstract
This study investigated possible sex-related differences in levels of antinociception and the rate of development of tolerance to the antinociceptive effects following prolonged (48 h) intravenous (i.v.) morphine administration in the rat. Groups of adult intact male, castrated male, female, and testosterone-pretreated female Sprague-Dawley rats received prolonged (48 h) infusions of i.v. morphine (5 or 10 mg/day) plus intra-arterial (i.a.) saline or i.v. morphine (5 mg/day) plus i.a. chloramphenicol (300 mg/day). Antinociception was quantified using the hotplate test. Serum concentrations of morphine and morphine-3-glucuronide (M3G) were assayed using high performance liquid chromatography with electrochemical detection, whereas the serum testosterone concentrations were quantified using an enzyme-linked immunosorbent assay method. Consistent with our previous findings in intact male rats, prolonged coinfusion of chloramphenicol with morphine produced a marked increase in the extent and duration of morphine antinociception in all experimental groups. Additionally, female and castrated male rats developed tolerance more slowly than either intact male or testosterone-pretreated female rats, when coinfused with parenteral morphine plus chloramphenicol. However, mean levels of antinociception were not significantly correlated with either the mean serum morphine or M3G concentrations, but were significantly inversely correlated with the mean values of the M3G/morphine serum molar concentration ratio. Testosterone pretreatment of female rats for 1 week before chronic morphine infusion abolished antinociception and markedly reduced both the serum morphine and M3G concentrations. These latter findings imply that testosterone modulates antinociception evoked by prolonged morphine infusion in rats via a mechanism that appears to involve modulation of morphine metabolism.
Footnotes
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Send reprint requests to: Associate Professor Maree T. Smith, School of Pharmacy, The University of Queensland, St. Lucia, Brisbane, Queensland, Australia 4072. E-mail:m.smith{at}pharmacy.uq.edu.au
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S.M.S. was supported by a Ph.D. Scholarship funded by the Australian Pain Society and the Australian Pain Relief Association. M.L. was supported by a Vacation Scholarship funded by Pharmaceutical Defense Limited. This research was supported by the National Health and Medical Research Council of Australia. Parts of this research were presented in abstract form at the 9th World Congress on Pain in Vienna, Austria, in 1999.
- Abbreviations:
- AUC
- area under the curve
- CNS
- central nervous system
- M3G
- morphine-3-glucuronide
- M6G
- morphine-6-glucuronide
- MOR AUC
- area under the serum morphine versus time curve
- %MPE
- percentage maximum possible antinociceptive effect
- SD
- Sprague-Dawley
- UGT
- UDP-glucuronosyltransferase
- Received July 31, 2000.
- Accepted December 13, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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