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 t o 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 en hancing morphine antinociception and/or delaying the development of antinoc iceptive tolerance. Parenteral chloramphenicol was given acutely (3-h studi es) or chronically (48-h studies). Morphine was administered by the i.v. or i.c.v. route. Control rats received chloramphenicol and/or vehicle. Antino ciception was quantified using the hotplate latency test. Coadministration of chloramphenicol with i.v. but not i.cv. morphine increased the extent an d duration of morphine antinociception by approximate to 5.5-fold relative to rats that received i.v. morphine alone. Thus, the mechanism through whic h chloramphenicol enhances i.v. morphine antinociception in the rat does no t directly involve supraspinal opioid receptors. Acutely, parenteral coadmi nistration of chloramphenicol and morphine resulted in an approximate to 75 % increase in the mean area under the serum morphine concentration-time cur ve but for chronic dosing there was no significant change in this curve, in dicating that factors other than morphine concentrations contribute signifi cantly to antinociception. Antinociceptive tolerance to morphine developed more slowly in rats coadministered chloramphenicol, consistent with our pro posal that in vivo inhibition of M3G formation would result in increased an tinociception and delayed development of tolerance. However, our data also indicate that chloramphenicol inhibited the biliary secretion of M3G. Wheth er chloramphenicol altered the passage of M3G and morphine across the blood -brain barrier remains to be investigated.