THE EFFECT OF OLD-AGE ON THE DISPOSITION AND ANTINOCICEPTIVE RESPONSEOF MORPHINE AND MORPHINE-6-BETA-GLUCURONIDE IN THE RAT

The aims of this study were to examine the effect of old age on the ph armacokinetics of morphine and morphine-6 beta-glucuronide (M6G) and t heir relationships to antinociceptive activity. Morphine (21.0 mu mol/ kg) or M6G (21.7 mu mol/kg) were administered s.c. to young adult and aged male Hooded-Wistar rats. Antinociceptive effect was measured by t he rail-flick method at various times up to 2.5 h or 6.5 h after morph ine or M6G administration, respectively, and concentrations of morphin e, morphine-3 beta-glucuronide (M3G) and M6G in plasma and brain were determined by HPLC. Creatinine clearance was significantly lower by 33 % or 21% in aged compared to young adult rats receiving morphine or M6 G, respectively. After morphine administration, the areas under the (i ) antinociceptive effect-time curve, (ii) plasma morphine concentratio n-time curve, and (iii) brain morphine concentration time curve were n ot different between young adult and aged rats. However, the AUC for p lasma M3G was five-fold higher in the aged relative to young adult rat s, which could not be accounted for by only a 33% lower creatinine cle arance. M6G was not detected in any plasma or brain sample from rats a dministered morphine and no M3G was detected in brain. For M6G adminis tration, the areas under the (i) antinociceptive effect-time curve, an d (ii) plasma M6G concentration-time curve were 1.8- and 1.6-fold high er in aged compared to young adult rats, respectively. Concentrations of M6G in brain were below the limit of quantification. No morphine or M3G was detected in any of the plasma or brain samples of rats admini stered M6G. The results demonstrate no change in morphine antinocicept ion and pharmacokinetics with age, and suggest that blood-brain barrie r permeability and receptor sensitivity to morphine are not altered in aged rats. Accumulation of M3G in plasma of aged rats is probably due to diminished renal clearance of M3G in addition to a reduction in th e biliary excretion of M3G. The heightened sensitivity of the aged rat s to M6G is probably due to the observed altered kinetics of M6G rathe r than a pharmacodynamic change. (C) 1997 International Association fo r the Study of Pain.