Enkephalin, a natural ligand for opiate receptors is composed of the pentapepides H-Tyr-Gly-Gly-Phe-Met-OH and H-Tyr-Gly-Gly-Phe-Leu-OH. The evidence is based on the determination of the amino acid sequence of natural enkephalin by the dansyl-Edman procedure and by mass spectrometry followed by synthesis and comparison of the natural and synthetic peptides.

Identification of two related pentapeptides from the brain with potent opiate agonist activity

Relief of intractable pain was produced in six human patients by stimulation of electrodes permanently implanted in the periventricular and periaqueductal gray matter. The level of stimulation sufficient to induce pain relief seems not to alter the acute pain threshold. Indiscriminate repetitive stimulation produced tolerance to both stimulation-produced pain relief and the analgesic action of narcotic medication; this process could be reversed by abstinence from stimulation. Stimulation-produced relief of pain was reversed by naloxone in five out of six patients. These results suggest that satisfactory alleviation of persistent pain in humans may be obtained by electronic stimulation.

https://science.sciencemag.org/content/sci/197/4299/183.full.pdf

Pain relief by electrical stimulation of the central gray matter in humans and its reversal by naloxone.

Analgesia produced by focal electrical stimulation of the brain is partially reversed by the narcotic antagonist naloxone. The absence of complete reversal does not appear to be caused by inadequate doses of naloxone since doses higher than 1 milligram per kilogram of body weight did not increase the antagonism. It is suggested that stimulation-produced analgesia may result, at least in part, from release of an endogenous, narcotic-like substance, such as that recently reported by other investigators.

https://science.sciencemag.org/content/sci/191/4230/961.full.pdf

Antagonism of stimulation-produced analgesia by naloxone, a narcotic antagonist

Molecular Neurobiology of the Mammalian Brain

https://science.sciencemag.org/content/sci/193/4258/1081.full.pdf

Terry Smith

Papers

Purification and properties of enkephalin - the possible endogenous ligand for the morphine receptor