Abstract
Chloramphenicol, an in vitro inhibitor of the glucuronidation of morphine to its putative antianalgesic metabolite, morphine-3-glucuronide (M3G), was coadministered with morphine in adult male Sprague-Dawley rats to determine whether it inhibited the in vivo metabolism of morphine to M3G, thereby enhancing morphine antinociception and/or delaying the development of antinociceptive tolerance. Parenteral chloramphenicol was given acutely (3-h studies) or chronically (48-h studies). Morphine was administered by the i.v. or i.c.v. route. Control rats received chloramphenicol and/or vehicle. Antinociception was quantified using the hotplate latency test. Coadministration of chloramphenicol with i.v. but not i.cv. morphine increased the extent and duration of morphine antinociception by ≈5.5-fold relative to rats that received i.v. morphine alone. Thus, the mechanism through which chloramphenicol enhances i.v. morphine antinociception in the rat does not directly involve supraspinal opioid receptors. Acutely, parenteral coadministration of chloramphenicol and morphine resulted in an ≈75% increase in the mean area under the serum morphine concentration-time curve but for chronic dosing there was no significant change in this curve, indicating that factors other than morphine concentrations contribute significantly to antinociception. Antinociceptive tolerance to morphine developed more slowly in rats coadministered chloramphenicol, consistent with our proposal that in vivo inhibition of M3G formation would result in increased antinociception and delayed development of tolerance. However, our data also indicate that chloramphenicol inhibited the biliary secretion of M3G. Whether chloramphenicol altered the passage of M3G and morphine across the blood-brain barrier remains to be investigated.
Footnotes
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Send reprint requests to: Maree T. Smith, School of Pharmacy, The University of Queensland, St. Lucia, Brisbane, Queensland, 4072, Australia. E-mail: maree.smith{at}pharmacy.uq.edu.au
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↵1 Parts of this research were presented in Abstract form at the National Scientific Conferences of ASCEPT (Australasian Society for Clinical and Experimental Pharmacologists and Toxicologists) and APSA (Australasian Pharmaceutical Sciences Association) in 1994 and 1996, respectively.
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M.Y.C.L.-F. was supported in part by a scholarship funded by AIDAB (Australian International Development Assistance Bureau). A.W.E.W. and this research were supported financially by the Queensland Cancer Fund. M.L. was supported in part by a Vacation Scholarship funded by Pharmaceutical Defense Limited. This research was also supported financially by The University of Queensland Research Grants Scheme.
- Abbreviations used are::
- SD
- Sprague-Dawley
- AUC
- area under the serum morphine and M3G concentration-time curve
- CNS
- central nervous system
- M3G
- morphine-3-glucuronide
- M6G
- morphine-6-glucuronide
- %MPE
- percentage of maximum possible antinociceptive effect
- %MPE AUC
- area under the %MPE versus time curve (extent and duration of antinociception)
- Received May 20, 1999.
- Accepted September 29, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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