ANTINOCICEPTION VERSUS SERUM CONCENTRATION RELATIONSHIPS FOLLOWING ACUTE ADMINISTRATION OF INTRAVENOUS MORPHINE IN MALE AND FEMALE SPRAGUE-DAWLEY RATS: DIFFERENCES BETWEEN THE TAIL FLICK AND HOT PLATE NOCICEPTIVE TESTS

Antinociception versus serum morphine concentration relationships were defined in male and female Sprague-Dawley rats administered single intravenous (i.v.) bolus doses of morphine, using the hot plate (2.1-14 mg/kg) and tail flick tests (1-8 mg/kg). Serum concentrations of morphine and morphine-3-glucuronide (M3G), its major metabolite in the rat, were assayed using high-performance liquid chromatography (HPLC) with electrochemical detection. Significantly higher (P < 0.05) values of peak antinociception (approximately 1.7-fold), as well as the extent and duration of antinociception (approximately fourfold), were observed in male compared with female rats administered 10 mg/kg morphine in the hot plate test. Although there were no significant sex-related differences in the area under the serum morphine concentration versus time curve (AUC) at this dose, systemic exposure to M3G (M3G AUC) was significantly higher (approximately twofold; P < 0.05) in female than male rats. In contrast with most previous studies investigating sex differences in morphine antinociception in rats, the antinociceptive effects of single i.v. doses of morphine (1-8 mg/kg) in the tail flick test did not differ significantly between male and female rats. Morphine ED50 and EC50 values (95% confidence intervals) for antinociception in the hot plate test were significantly lower (P < 0.05) in male rats (ED50 8.4 mg/kg (7.6-9.2); EC50 1.8 nmol/L (1.5-2.1)) compared with female rats (ED50 10.6 mg/kg (9.1-12.0); EC50 3.7 nmol/L (3.4-4.1)). However, in the tail flick test, there was no significant difference between male and female rats in ED50 (1.8 (0.4-3.3) and 1.4 mg/kg (0.4-2.5), respectively) or EC50 (0.5 (0.3-0.6) and 0.4 nmol/L (0.2-0.5), respectively) values. Supraspinal attenuation of morphine antinociception by M3G may account for these differences.