Studies on the mechanism of the interaction of narcotic analgesics with brain serotonin

Morphine, pentazocine, methadone and pethidine were tested for their ability to modify serotonin metabolism and the depletion of serotonin induced by fenfluramine in the rat forebrain and brainstem. Their analgesic effect was also studied in animals with electrolytic lesions of the nucleus medianus raphe. Except for a reduction of the effect of fenfluramine on brainstem serotonin by the highest dose of pethidine (30 mg/kg), none of the narcotics examined, unlike chlorimipramine, counteracted the depletion of serotonin induced by fenfluramine in forebrain and brainstem. Increased levels of 5-hydroxy-indoleacetic acid in the forebrain and brainstem were found in animals treated with morphine, whereas pentazocine increased serotonin metabolism only in the forebrain. Of methadone and pethidine only the latter significantly decreased serotonin metabolism in the brainstem. All the compounds examined had less analgesic effect in rats with electrolytic lesions of the nucleus medianus raphe. These findings indicate a complex but significant interaction between the various narcotic analgesics and brain serotonin but are against a relationship between their analgesic activity and their inhibition of serotonin uptake into central neurons.