S. M. South

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

1 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). 2 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. 3 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. 4 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. 5 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. 6 Supraspinal attenuation of morphine antinociception by M3G may account for these differences.