Recent Advances in the Search for the μ-Opioidergic System: The Antinociceptive Properties of Endomorphin-1 and Endomorphin-2 in the Mouse

Abstract

Two highly selective μ-opioid receptor agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2), have been identified and postulated to be endogenous μ-opioid receptor ligands. The present minireview describes the antinociceptive properties with the tail-flick test of these two ligands given intra-cerebroventricularly (i.c.v.) and intrathecally (i.t.) in ICR mice. EM-1 or EM-2 given i.c.v. or i.t. dose-dependently produce antinociception. These antinociceptive effects induced by EM-1 and EM-2 given i.c.v. or i.t. are selectively mediated by the stimulation of μ-, but not δ- or κ-opioid receptors. Like other μ-opioid agonists morphine and DAMGO ([D-Ala2,NMePhe4,Gly5-ol]enkephalin), EM-1 and EM-2 given i.c.v. activate descending pain controls by the releases of noradrenaline and 5-HT and subsequently act on α2-adreno-ceptors and 5-HT receptors, respectively, in the spinal cord to produce antinociception. However, the antinociception induced by EM-2 given i.c.v. or i.t. also contain an additional component, which is mediated by the release of dynorphin A(1 - 17) acting on κ-opioid receptors at the supraspinal and spinal sites. In addition, the antinociception induced by EM-2 given i.c.v. contains another component, which is mediated by the release of Met-enkephalin acting on δ2-opioid receptors in the spinal cord. It is proposed that there are two subtypes of μ-opioid receptors,which are involved in EM-1- and EM-2-induced antinociception. One subtype of μ-opioid receptors is stimulated by EM-1, EM-2 and other μ-opioid agonists morphine and DAMGO; and another subtype of μ-opioid is sorely stimulated by EM-2 and is involved in the releases of dynorphin A(1 - 17) and Met-enkephalin for the production of antinociception.