Intracerebroventricular (40-80 microgram) or i.p. (5-20 mg/kg) injection of leucine enkephalin 15 min before or after s.c. morphine administration resulted in a marked, dose-dependent enhancement of morphine analgesia as measured by the mouse tail-flick assay. Further, i.p. injection of leucine enkephalin (5 mg/kg) enhanced the analgesia produced by methadone and levorphanol in the tail-flick assay but not that by nalorphine in the abdominal constriction assay. Met- but not leu-enkephalin was an active analgesic in the abdominal constriction assay with the doses used. (D-Ala2, D-leu5)-enkephalin (1 mg/kg) treatment also markedly enhanced morphine analgesia. Similarly, administration of leucine enkephalin enhanced the development of acute tolerance and dependence produced by a single dose of morphine. Methionine enkephalin had no effect on any of the pharmacological responses produced by morphine, methadone or levorphanol. Morphine brain levels of mice after treatment with leucine or methionine enkephalin were found to be no different than those of saline-treated control animals. These results suggest that leucine enkephalin may be an important and potent physiological modulator of narcotic efficacy.