Endomorphin-1

The antinociceptive properties of endomorphin-1 and endomorphin-2 in the mouse

Two highly selective mu-opioid receptor agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2), have been identified and postulated to be endogenous mu-opioid receptor ligands. The present minireview describes the antinociceptive properties with the tail-flick test of these two ligands given intracerebroventricularly (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 mu-, but not delta- or kappa-opioid receptors. Like other mu-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 alpha2-adrenoceptors 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 kappa-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 delta2-opioid receptors in the spinal cord. It is proposed that there are two subtypes of mu-opioid receptors,which are involved in EM-1- and EM-2-induced antinociception. One subtype of mu-opioid receptors is stimulated by EM-1, EM-2 and other mu-opioid agonists morphine and DAMGO; and another subtype of mu-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.

From MIF-1 to endomorphin: the Tyr-MIF-1 family of peptides

The Tyr-MIF-1 family of small peptides has served a prototypic role in the introduction of several novel concepts into the peptide field of research. MIF-1 (Pro-Leu-Gly-NH(2)) was the first hypothalamic peptide shown to act "up" on the brain, not just "down" on the pituitary. In several situations, including clinical depression, MIF-1 exhibits an inverted U-shaped dose-response relationship in which increasing doses can result in decreasing effects. This tripeptide also can antagonize opiate actions, and the first report of such activity also correctly predicted the discovery of other endogenous antiopiate peptides. The tetrapeptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH(2)) not only shows antiopiate activity, but also considerable selectivity for the mu-opiate binding site. Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH(2)) is an even more selective ligand for the mu receptor, leading to the discovery of two more Tyr-Pro tetrapeptides that have the highest specificity and affinity for this site. These are the endomorphins: endomorphin-1 is Tyr-Pro-Trp-Phe-NH(2) and endomorphin-2 is Tyr-Pro-Phe-Phe-NH(2). Tyr-MIF-1 proved, contrary to the then prevailing dogma, that peptides can be saturably transported across the blood-brain barrier by a quantifiable transport system. Unexpectedly, the Tyr-MIF-1 transporter is shared with Met-enkephalin. In the era in which it was doubtful whether a peripheral peptide could exert CNS effects, the Tyr-MIF-1 family of peptides also explicitly showed that they can exert more than one central action that persists longer than their half-lives in blood. These peptides clearly illustrate that the name of a peptide restricts neither its actions nor its conceptual implications.

Endomorphin-1 and endomorphin-2: pharmacology of the selective endogenous mu-opioid receptor agonists

The recently discovered endogenous opioid peptides, endomorphins-1 and -2, appear to have properties consistent with neurotransmitter/neuromodulator actions in mammals. This review surveys the information gained so far from studies of different aspects of the endomorphins. Thus, the endomorphins have been found unequally in the brain; they are stored in neurons and axon terminals, with a heterogeneous distribution; they are released from synaptosomes by depolarization; they are enzymatically converted by endopeptidases; and they interact specifically and with high affinity with mu-opioid receptors. The most outstanding effect of the endomorphins is their antinociceptive action. This depends on both central and peripheral neurons. Additionally, the endomorphins cause vasodilatation by stimulating nitric oxide release from the endothelium. Their roles in different central and peripheral functions, however, have not been fully clarified yet. From a therapeutic perspective, therefore, they may be conceived at present as potent antinociceptive and vasodilator agents.

Endomorphin-induced motivational effect: differential mechanism of endomorphin-1 and endomorphin-2

The newly discovered endogenous mu-opioid receptor (MOP-R) ligands endomorphin-1 (EM-1) and -2 (EM-2) exhibit the highest specificity and affinity for the MOP-R of any endogenous substance so far described in the mammalian nervous system. This review focuses on differential mechanism of the motivational effects induced by EM-1 and EM-2. In the [35S]GTPgammaS binding assay, either EM-1 or EM-2 causes a concentration-dependent G-protein activation in brain membrane of normal mice, whereas neither EM-1 nor EM-2 produces any activation of G-protein in membranes obtained from the MOP-R knockout mice. These results provide direct evidence at the molecular level that both EMs act on the MOP-R as the endogenous MOP-R agonists. Based on the conditioned place preference paradigm in mice, EM-1 given intracerebroventriculally produced a dose-related place preference. This effect was abolished by pretreatment with the MOP-R antagonist beta-funaltrexamine (FNA) but not the delta-opioid receptor (DOP-R) antagonist naltrindole and the kappa-opioid receptor (KOP-R) antagonist nor-bialtorphimine (BNI). Unlike EM-1, EM-2 exhibited a place aversion. The aversive effect was inhibited by not only beta-FNA but also nor-BNI. Place aversion produced by EM-2 was also attenuated by pretreatment with an antiserum against an endogenous KOP-R ligand dynorphin A(1-17). These findings indicate that EM-1 may produce its rewarding effect via MOP-Rs. Furthermore, the aversive effect induced by EM-2 may be associated with the stimulation of the EM-1-insensitive MOP-R subtype and necessarily activate an endogenous KOPergic system in the mouse brain.

Differential antinociceptive effects induced by intrathecally-administered endomorphin-1 and endomorphin-2 in mice

Two highly selective mu-opioid receptor (MOP-R) agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2), have been identified and postulated to be endogenous ligands for MOP-R. Experiments were designed to determine the involvement of subtypes of MOP-R on the antinociceptive effects of EM-1 or EM-2 using the paw withdrawal test. The intrathecal (i.t.) injection of EM-1 and EM-2 produced dose-dependent antinociception in mice 1 min after the injection. Subcutaneous (s.c.) pretreatment with naloxonazine (NLZ), a selective MOP1-R antagonist, dose-dependently antagonized the antinociceptive effect of EMs. The antinociceptive effect of EM-2 was more sensitive to NLZ than that of EM-1. The selective heroin/morphine-6beta-glucuronide antagonist 3-methoxynaltrexone (3-MNT) blocked EM-2-induced antinociception, but not EM-1-induced antinociception. The dose-response curve of EM-2 was shifted threefold to the right by pretreatment with s.c. 3-MNT at a dosage of 0.25 mg/kg. EM-2-induced antinociception was attenuated by pretreatment with s.c. nor-binaltorphimine and naltrindole, whereas the effect of EM-1 was not affected. Moreover, the antinociceptive effect of EM-2 was attenuated by i.t. pretreatment with antisera against dynorphin A(1-17) or methionine-enkephalin. These results suggest that EM-2-induced antinociception may be mediated by the subtype of MOP-R, which is sensitive to NLZ and 3-MNT, and by subsequent release of dynorphin A(1-17) and methionine-enkephalin in the spinal cord.