1. The aims of the present study were to administer
morphine (14.0 mumol/kg, s.c.) to male Hooded Wistar rats and to determine the effect of
uranyl nitrate-induced
renal failure on: (i) the antinociceptive effect of
morphine; (ii) the pharmacokinetics of
morphine and
morphine-3-glucuronide (M3G); and (iii) the relationship between antinociceptive effect and the pharmacokinetics of
morphine in plasma and brain. 2.
Renal failure was induced by a single s.c. injection of
uranyl nitrate and kinetic/dynamic studies were performed 10 days after its administration, when
creatinine clearance was 17% of the control group. Antinociceptive effect was measured by the tail-flick method at various times up to 2 h post-
drug administration. Concentrations of
morphine and M3G in plasma and brain and concentrations of
creatinine in urine and serum were determined by specific HPLC methods. 3. After
morphine administration, the area under the antinociceptive effect-time curve was decreased by 44% in
renal failure rats. There were no differences between control and
renal failure rats in: (i) plasma
morphine concentration-time curves; (ii) brain
morphine concentration-time curves; and (iii) plasma M3G concentration-time curves.
Morphine-6-glucuronide was not detected in any plasma or brain sample from rats administered
morphine and no M3G was detected in brain. 4. For both control and
renal failure rats, the relationships between antinociceptive effect and plasma
morphine concentration were characterized by counterclockwise hysteresis loops, probably reflecting a delay for the relatively polar
morphine to cross the blood-brain barrier. The relationship between antinociceptive effect and brain
morphine concentration in control rats revealed no evidence of acute tolerance and was described by a sigmoidal function. In contrast, the relationship in
renal failure rats was characterized by clockwise hysteresis, which is consistent with acute tolerance development.