Sex differences in the antinociceptive effect of codeine and its peripheral but not central metabolism in adult mice

Codeine is a natural opiate extracted from opium poppy (Papaver somniferum) and used to alleviate mild to moderate pain. The analgesic effect of this molecule results from its metabolism into morphine which is an agonist of the mu opioid receptor. Morphine's major metabolite morphine-3-glucuronide induces both thermal and mechanical hypersensitivies while codeine-6-glucuronide has been proposed to be antinociceptive. However, sex differences in codeine antinociceptive effect and pharmacokinetics were barely studied. To this purpose, we injected male and female mice with codeine (2.5, 5, 10, 20 and 40 mg/kg) and thermal hypersensitivity was assessed 30 min after injection using the Tail Immersion Test. Moreover, both peripheral and central metabolism of codeine were evaluated respectively in the blood or pain-related brain structures in the central nervous system. The amounts of codeine and its metabolites were quantified using the isotopic dilution method by liquid chromatography coupled to a mass spectrometer. Our results show that codeine induces a greater antinociceptive effect in males than females mice independently of the estrous cycle. Moreover, major sex differences were found in the peripheral metabolism of this molecule, with higher amounts of pronociceptive morphine-3-glucuronide and less antinociceptive codeine-6-glucuronide in females than in males. Concerning the central metabolism of codeine, we did not find significant sex differences in pain-related brain structures. Collectively, these findings support a greater codeine antinociceptive effect in males than females in mice. These sex differences could be influenced by a higher peripheral metabolism of this molecule in female mice rather than central metabolism.