Systemic coadministration of chloramphenicol with intravenous but not intracerebroventricular morphine markedly increases morphine antinociception and delays development of antinociceptive tolerance in rats.
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 approximately 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 approximately 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.
Smith
M T
MT
School of Pharmacy, The University of Queensland, St. Lucia, Brisbane, Queensland, Australia. maree.smith@pharmacy.uq.edu.au
Nielsen
C K
CK
Lim-Fraser
M Y
MY
Wright
A W
AW
Lau
M
M
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D002701:Chloramphenicol / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004361:Drug Tolerance; D005263:Femoral Artery; D020719:Glucuronides / Q000378:metabolism; D007202:Indicators and Reagents; D007263:Infusions, Parenteral; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D007601:Jugular Veins; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000097:blood; D010147:Pain Measurement / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000701:Analgesics, Opioid; D020719:Glucuronides; D007202:Indicators and Reagents; D009022:Morphine Derivatives; D011500:Protein Synthesis Inhibitors; D002701:Chloramphenicol; D009020:Morphine; C018108:morphine-3-glucuronide