When the histamine (HA) turnover in the brain of mice was estimated on the basis of the pargyline-induced accumulation of tele-methylhistamine (t-MH), a predominant metabolite of brain HA, the enhancing effect of phencyclidine (PCP) on the HA turnover was antagonized by a large dose of naloxone. However, a dopamine receptor antagonist haloperidol, which is also a potent sigma receptor antagonist, did not inhibit the effect of PCP on the HA turnover. [D-Ala2,D-Leu5]enkephalin, a prototypic delta opioid agonist, markedly enhanced the HA turnover. The effect of this peptide was demonstrated not only when the HA turnover was determined by the pargyline-induced t-MH accumulation but when it was estimated by the HA depletion induced by alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase. A sigma agonist, SKF-10047, and a kappa agonist, ethylketazocine, had no PCP-like enhancing effect on the HA turnover. These results suggest that PCP enhances the brain HA turnover in mice by stimulating, probably indirectly, endogenous opioid systems.