The effects of i.c.v. injected selective ligands for mu and delta opioid receptors on histamine (HA) turnover in the mouse brain were investigated to determine the receptor subclasses involved in the neurochemical response to opioids. HA turnover was measured by the accumulation of tele-methylhistamine, a major metabolite of brain HA, after pargyline injection (65 mg/kg i.p.). The increase in the HA turnover induced by [D-Ala2,D-Leu5] enkephalin (0.5 microgram i.c.v.) was antagonized by naloxone (0.3 microgram i.c.v.) but not by ICI 174,864 (5 micrograms i.c.v.), a selective delta receptor antagonist. [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAGO; 0.1-0.5 microgram i.c.v.), a selective mu receptor agonist, produced an increase in the HA turnover, whereas [D-Thr2-Leu5]enkephalin, Thr (0.1-1.0 microgram i.c.v.), a selective delta receptor agonist, had little effect on the HA turnover. DAGO (0.1 microgram i.c.v.) also increased the steady-state level of tele-methylhistamine but not that of HA. The effect of DAGO was observed in various brain regions except for the hypothalamus, and it was the most marked in the striatum. DAGO (10(-7) and 10(-6) M) significantly increased the K+ (30 mM)-evoked HA release from mouse cerebral cortical slices without influencing on the spontaneous HA release. The enhancement of HA release induced by DAGO (10(-6) M) was blocked completely by naloxone (10(-6) M) but not by tetrodotoxin (10(-6) M). These results suggest that opioids with mu agonist activity increase brain HA turnover by facilitating HA release from nerve endings.