Jpn. J. Pharmacol. 76 (3), 233-253 (1998)


Evidence for the Existence of the beta-Endorphin-Sensitive "epsilon-Opioid Receptor" in the Brain: The Mechanisms of epsilon-Mediated Antinociception

Minoru Narita and Leon F. Tseng (*)



Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, Wisconsin 53226, U.S.A.
(*) To whom all correspondence should be addressed.

Abstract: Recently, mu-,delta-and kappa-opioid receptors have been cloned and relatively well-characterized. In addition to three major opioid receptor types, more extensive studies have suggested the possible existence of other opioid receptor types that can be classified as non-mu, non-delta and non-kappa. Based upon anatomical and binding studies in the brain, the sensitive site for an endogenous opioid peptide, beta-endorphin, has been postulated to account for the unique characteristics of the opioid receptor defined as a putative epsilon-opioid receptor. Many epsilon-opioid receptors are functionally coupled to G-proteins. The functional epsilon-opioid receptors in the brain are stimulated by bremazocine and etorphine as well as beta-endorphin, but not by selective mu-, delta- or kappa-opioid receptor agonists. epsilon-Opioid receptor agonists injected into the brain produce profound antinociception. The brain sites most sensitive to epsilon-agonist-induced antinociception are located in the caudal medial medulla such as the nucleus raphe obscures, nucleus raphe pallidus and the adjacent midline reticular formation. The stimulation of epsilon-opioid receptors in the brain facilitates the descending enkephalinergic pathway, which probably originates from the brainstem terminating at the spinal cord. The endogenous opioid Met-enkephalin, released in the spinal cord by activation of supraspinal epsilon-opioid receptors, stimulates spinal delta2-opioid receptors for the production of antinociception. It is noteworthy that the epsilon-opioid receptor-mediated pain control system is different from that of other opioid systems. Although there appears to be no epsilon-selective ligand currently available, these findings provide strong evidence for the existence of the putative epsilon-opioid receptor and its unique function in the brain.


Keywords: epsilon-Opioid receptor, beta-Endorphin, Descending enkephalinergic pathway, Antinociception


Copyrightę The Japanese Pharmacological Society 1998

[Back to TOC]