Genetic variability in morphine sensitivity and tolerance between different strains of rats

The development of tolerance, the sensitivity to morphine and the effective morphine plasma concentrations have been studied in Sprague-Dawley (SD-U) and Wistar (W) rats. Daily administration of morphine (10 mg/kg/12 h for 9 days) in W rats produced a reduction in morphine antinociception from day 1 (12+/-0 s) to day 9 (6.7+/-1.9 s). Morphine antinociception in the SD-U rats did not change over the period of treatment. Naloxone abolished the antinociception of morphine in both opiate naive and chronically treated SD-U rats. The pharmacokinetic parameters of morphine and morphine-3-glucuronide did not differ significantly between strains. Both naive and chronically treated SD-U rats required smaller doses of morphine than W rats to obtain a maximum antinociceptive effect. Plasma concentrations following administration of the same dose of morphine, did not differ between strains or days of treatment. The range of morphine concentrations required to obtain a maximum effect were lower in SD-U rats, both on day 1 and day 8 when compared to W rats. These results show differences between the two strains with regard to both morphine sensitivity and development of tolerance, whilst also suggesting that the differences do not have a kinetic basis. (C) 2000 Elsevier Science B.V. All rights reserved.