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International audience; Background and Purpose-In rodents, morphine antinociception is influenced by sex. However, conflicting results have been reported regarding the interaction between sex and morphine antinociceptive tolerance. Morphine is metabolised in the liver and brain into morphine-3-glucuronide (M3G). Sex differences in morphine metabolism and differential metabolic adaptations during tolerance development might contribute to behavioural discrepancies. This article investigates the differences in peripheral and central morphine metabolism after acute and chronic morphine treatment in male and female mice. Experimental Approach-Sex differences in morphine antinociception and tolerance were assessed using the tail-immersion test. After acute and chronic morphine treatment, morphine and M3G metabolic kinetics in the blood were evaluated using LC-MS/MS. In addition, they were quantified in several central nervous system (CNS) regions. Finally, the blood-brain barrier (BBB) permeability of M3G was assessed in male and female mice. Key Results-This study demonstrated that female mice showed weaker morphine antinociception and faster induction of tolerance than males. Additionally, female mice showed higher levels of M3G in the blood and several pain-related CNS regions than male mice, whereas lower levels of morphine were observed in these regions. M3G brain/blood ratios after injection of M3G indicated no sex differences in M3G BBB permeability, and these ratios were lower than those obtained after injection of morphine. Conclusion-These differences are attributable mainly to morphine central metabolism, which differed between males and females in pain-related CNS regions, consistent with weaker morphine antinociceptive effects in females. However, the role of morphine metabolism in antinociceptive tolerance seemed limited.

Morphine effects are influenced by sex. In rodents, morphine metabolism involves its glucuronidation to morphine-3-glucuronide (M3G). Interestingly, M3G has been shown to produce hyperalgesia. M3G pronociceptive effect could oppose morphine-induced antinociception. Morphine potency was higher in males than females and morphine antinociceptive tolerance developed earlier in females during the protocol. M3G pronociceptive effect did not seem to be influenced by sex. Morphine and M3G were quantified in the blood and some pain-related brain regions after morphine injection. The M3G/morphine metabolic ratios were dramatically higher in females than in males. In vivo central metabolism of morphine was observed. To conclude, peripheral and central metabolism of morphine are influenced by sex and central metabolism could participate in the sex differences observed in morphine antinociception. However, its implication seems limited during the induction of morphine antinociceptive tolerance., Les effets de la morphine sont influencés par le sexe. Chez le rongeur, son métabolisme implique sa glucuronidation en morphine-3-glucuronide (M3G). La M3G provoque une hyperalgésie qui pourrait s’opposer aux effets antinociceptifs de la morphine. Nous avons constaté que l’antinociception induite par la morphine est plus forte chez la souris mâle et que la tolérance antinociceptive se développe plus rapidement chez la souris femelle. La M3G possède un effet pronociceptif qui ne semble pas dépendre du sexe. Nous avons quantifié la morphine et la M3G dans le sang et dans des régions cérébrales impliquées dans le contrôle de la douleur après une injection de morphine, et nous avons constaté que les ratios métaboliques M3G/morphine étaient largement supérieurs chez les femelles. Nous avons également observé un métabolisme central de la morphine in vivo. Nous avons conclu que le métabolisme périphérique et central était influencé par le sexe et que le métabolisme central de la morphine pourrait participer aux différences d’antinociception liées au sexe. Cependant, son implication dans la tolérance antinociceptive semble limitée.