The metabolic disposition of radiolabeled enkephalins in vitro and in situ

F. B. Craves, P. Y. Law, C. A. Hunt, H. H. Loh

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The metabolism of met- and leu-enkephalin by brain fractions which the peptides might contact during isolation procedures and opiate stereospecific binding assays was assessed. Previous observations demonstrating susceptibility of enkephalins to rapid metabolism by brain tissues were confirmed and extended. The enzymatic activity was ubiquitous but non-membranous fractions were most active. Acidic pH (4.0) and lowering the temperature (0°) inhibited but did not prevent metabolism, nor did concentrations of bacitracin which enhance the activity of metenkephalin in in vitro opiate assays. Examination of the metabolites indicate the most rapid enzymatic attack in vitro is the tyr-gly bond. In order to determine the rate of met-enkephalin metabolism in vivo, [3H]met-enkephalin was administered either as bolus into the right lateral ventricle of rats or perfused through the rat ventricular system. The perfusate in both cases was collected from the cisterna magnum and the radiolabeled peptide was analyzed. In contrast to the in vitro studies, in situ the initial enzymatic attack is at the gly-gly or gly-phe bond rather than the terminal tyr-gly. Kinetic analysis of the perfused [3H]met-enkephalin demonstrated an apparent metabolic half-life of 3.9 min. The half-life is inconsistent with the hypothesis that the absence of significant enkephalin anti-nociceptive activity is due to its rapid metabolism by intact brain tissue. The data indicate it is unlikely that met-enkephalin serves a primary role as an endogenous analgesic peptide in the central nervous system.

Original languageEnglish (US)
Pages (from-to)492-506
Number of pages15
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - 1978
Externally publishedYes


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