A further characterization of the differential effects of leucine enkephalin, methionine enkephalin and their analogs on morphine-induced analgesia
Vaught, J.L.; Takemori, A.E.
Journal of Pharmacology and Experimental Therapeutics 211(2): 280-283
1979
ISSN/ISBN: 0022-3565 PMID: 501561 Document Number: 141229
Administration of leucine enkephalin i.p. (5 mg/kg) 15 min before or after s.c. morphine in mice resulted in a parallel shift of the morphine dose response curve to the left and a decrease in the analgesic ED50 to .apprx. 1/2 of saline-treated controls as measured by the tail-flick assay. Previous studies demonstrated that methionine enkephalin, at similar doses and routes of administration, has no effect on the morphine ED50. Naloxone administration (i.p., 1 mg/kg) 30 min before s.c. morphine and 15 min before i.p. leucine enkephalin completely blocked the potentiating effects of leucine enkephalin on morphine-induced analgesia. Intracerebroventricular (i.c.v.) injection of [D-Ala2,D-Leu5]-enkephalin (40-200 ng) or [D-Ala2]-met-enkephalinamide (2-6 .mu.g) produced a dose-dependent, naloxone-reversible analgesia with a peak onset and duration of action similar to i.c.v. morphine-induced analgesia. At a dose well below the minimum analgesic dose, i.c.v. injection of [D-Ala2,D-Leu5]-enkephalin (10 ng) 15 min before i.p. injection (1 mg/kg) or 15 min following s.c. morphine enhanced morphine analgesia markedly. At similar subanalgesic doses, [D-Ala2]-met-enkephalinamide was without effect. Leucine enkephalin (5 mg/kg i.p.) given 5 min before i.c.v. injection of [D-Ala2]-met-enkephalinamide resulted in a similar parallel shift of the [D-Ala2]-met-enkephalinamide dose-response curve to the left and a decrease in the analgesic ED50 to .apprx. 1/3 that of saline-treated controls. A single i.c.v. injection of methionine-enkephalin (100 .mu.g) which resulted in analgesia in 20% of the tested animals was potentiated similarly after i.p. leu-enkephalin (20 mg/kg) administration. The initial degradation product of leucine enkephalin, H2-Gly-Gly-Phe-Leu-OH was also 1/4-1/5 as potent as the parent pentapeptide in enhancing morphine analgesia. H2-Gly-Gly-Phe-Met-OH and H2-Phe-Leu-OH were devoid of potentiating activity at the doses used. The enhancement of morphine-induced analgesia by leucine enkephalin may be receptor mediated and dependent on the intact parent pentapeptide. This differential interaction between leucine enkephalin and methionine enkephalin with morphine raises the question of the possibility of differential physiological functions.