Brain peptides with opiate antagonist action: Their possible role in tolerance and dependence

Abstract

(1) Extracts of brain taken from rats injected with increasing doses of morphine acted like antagonists on the mouse vas deferens preparation in vitro and on morphine analgesia in vivo. (2) After electrophoretic fractionation, the antagonist properties were found among the basic peptides. One of these, Arg-Tyr-Gly-Gly-Phe-Met, was synthcsized and reproduced the analgesia-inhibiting effect of the brain extract. However, when tested on mouse vas deferens, it did not show antagonist properties but acted like enkephalin. (3) Quantitative estimation of the agonist and antagonist concentration in the brain of morphine-injected rats showed increase in both types of peptides during the first 12 days of treatment followed by a particularly marked fall of the agonists, far below the normal level. (4) Preliminary experiments have shown that the endogenous antagonists and the synthetic peptide can precipitate opiate withdrawal symptoms and may, therefore, be involved in the mechanism of dependence. (5) The results reported suggest the possibility that a shift in the balance of endogenous agonists and antagonists may contribute to the development of tolerance and dependence.