In vivo modulation of rat hypothalamic opioid peptide content by intracerebroventricular injection of guanidinoethylmercaptosuccinic acid (GEMSA): possible physiological role of enkephalin convertase.

Twice-daily intracerebroventricular (i.c.v.) injections for three days of increasing doses of guanidino-ethyl-mercapto-succinic acid (GEMSA) produced a dose-dependent decrease in methionine-enkephalin- and leucine-enkephalin levels in rat hypothalami. GEMSA is a specific and potent inhibitor of a carboxypeptidase B-like processing enzyme, referred to as enkephalin convertase (EC). The administration of GEMSA (0.1 microgram) resulted in more than 50% reduction in the levels of these two opioid peptides. However, no changes occurred in the hypothalamic content of beta-endorphin or dynorphin1-17. Moreover, in GEMSA-treated animals, hypothalamic luteinizing hormone-releasing hormone and serum luteinizing hormone levels were increased by 75%. Serum prolactin concentrations were decreased by 60% at the same time. Subcutaneous naloxone administration resulted in a 75% elevation of serum LH concentrations in control animals whereas GEMSA-treated animals showed a blunted response, most likely due to a decreased amount of opioid-active peptides. The present study is in agreement with the putative role of EC in the processing of the multivalent opioid precursor (proenkephalin A) in the rat hypothalamus. The enzyme inhibition by GEMSA may result in a reduced enkephalinergic tone, which is then accompanied by an altered endocrine status.