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