Evidence for epsilon-opioid receptor-mediated beta-endorphin-induced analgesia

Among the opioid receptors, which have been pharmacologically classified as mu, delta, kappa and epsilon, the existence of the epsilon receptor has been controversial, and this receptor is generally not recognized as a member of the opioid peptide receptor family because it has not been precisely characterized. However, results from pharmacological, physiological and opioid receptor binding studies clearly indicate the presence of epsilon-opioid receptors, which are distinct from mu-, delta- or kappa-opioid receptors. This putative epsilon-opioid receptor is stimulated supraspinally by the endogenous opioid peptide beta-endorphin, which induces the release of Met-enkephalin, which, in turn, acts on spinal delta2-opioid receptors to produce antinociception. In this article, this beta-endorphin-sensitive epsilon-opioid receptor-mediated descending pain control system, which is distinct from that activated by the mu-opioid receptor agonist morphine, is described and the physiological role of the beta-endorphin-mediated system in pain control activated by cold-water swimming and intraplantar injection of formalin is discussed.