Evidence for the existence of the beta-endorphin-sensitive "epsilon-opioid receptor" in the brain: the mechanisms of epsilon-mediated antinociception.
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.
Narita
M
M
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee 53226, USA.
Tseng
L F
LF
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism*; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009020:Morphine / Q000494:pharmacology; D005810:Multigene Family; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism*; D018847:Opioid Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D001615:beta-Endorphin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D018847:Opioid Peptides; D011957:Receptors, Opioid; C043460:epsilon receptor; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D001615:beta-Endorphin; D009020:Morphine; D019204:GTP-Binding Proteins