Morphine-induced increase in the brain and plasma concentrations of neuroactive steroids in the rat

The effects of acute and chronic administration of morphine on the brain and plasma concentrations of neuroactive steroids were examined in rats. A single intraperitoneal administration of morphine (5 to 30 mg/kg,) induced a dose- and time-dependent increase in the concentrations of progesterone, allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC) in the cerebral cortex of intact rats. The increases in the cerebrocortical concentrations of progesterone and allopregnanolone were already significant at the dose of 10 mg/kg (+ 104% and + 101%, respectively), and greatest at the dose of 30 mg/kg (+ 194%, + 161%, respectively) in rats killed 60 min after morphine administration. The increase in cerebrocortical concentration of THDOC was significant (+58%) at the dose of 20 mg/kg and greatest (+70%) at the dose of 30 mg/kg. Morphine also increased the plasma concentrations of these neuroactive steroids with a dose-response similar to that observed in the brain. Moreover, the brain and plasma concentrations of progesterone, allopregnanolone and THDOC were not affected by morphine in adrenalectomized-orchiectomized rats, suggesting that activation of the HPA axis mediates the effect of morphine on brain and plasma concentrations of neuroactive steroids. Finally, chronic administration of morphine (from 10 to 80 mg/kg, twice a day for 8 days) to intact animals did not affect the basal levels of progesterone, allopregnanolone and THDOC measured 12 and 24 h after the last drug administration. A challenge injection of morphine failed to modify the concentrations of these steroids in brain and plasma, indicating that repeated exposure to morphine induces tolerance to the steroidogenic action of morphine.