Abstract

This investigation was carried out to test the hypothesis that the brain contains a substance that functions as an endogenous mediator at central morphine receptor sites. The extraction and purification of a low molecular weight substance are described. This substance inhibits neurally evoked contractions of the mouse vas deferens and guinea pig myenteric plexus. The inhibitory action of this substance was antagonized by the 3 narcotic antagonists naloxone, naltrexone and MR 1302 at nanomolar concentrations. The narcotic antagonists alone had no effect on the assay tissues. The purified substance had no effect on the guinea pig or rabbit vas deferens, tissues which do not possess morphine receptor sites. The pharmacological activity of the substance is destroyed by carboxypeptidase and leucine aminopeptidase, it is hydrophilic and behaves as an ampholyte in ion exchange systems. These observations and the production of ninhydrin positive products on acid hydrolysis indicate the presence of a small molecular weight (less than 700) peptide. The morphine-like substance was unevenly distributed in the brain, the highest concentrations occurring in the striatum, midbrain, pons and medulla. No activity could be detected in extracts of cerebellum, liver or lung. It is suggested that the compound isolated in this investigation forms part of a central pain suppressive system and may also have a wider neurochemical role in the brain.