Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways

doi:10.1073/pnas.0605865103

Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways

*Laboratoire de Pharmacologie des Regulations Neuroendocrines, Institut Pasteur, 28 Rue du Docteur Roux, F-75724 Paris Cedex 15, France;
^†ETAP-Ethologie Appliquée, 13 Rue du Bois de la Champelle, F-54500 Vandoeuvre-lès-Nancy, France; and
^‡Investigation Clinique et Appui à la Recherche (ICARe), Centre Médicale, Institut Pasteur, 28 Rue du Docteur Roux, F-75724 Paris Cedex 15, France

Edited by Susan E. Leeman, Boston University School of Medicine, Boston, MA, and approved October 5, 2006 (received for review July 12, 2006)

Abstract

Mammalian zinc ectopeptidases play important roles in turning off neural and hormonal peptide signals at the cell surface, notably those processing sensory information. We report here the discovery of a previously uncharacterized physiological inhibitor of enkephalin-inactivating zinc ectopeptidases in humans, which we have named Opiorphin. It is a QRFSR peptide that inhibits two enkephalin-catabolizing ectoenzymes, human neutral ecto-endopeptidase, hNEP (EC 3.4.24.11), and human ecto-aminopeptidase, hAP-N (EC 3.4.11.2). Opiorphin displays potent analgesic activity in chemical and mechanical pain models by activating endogenous opioid-dependent transmission. Its function is closely related to the rat sialorphin peptide, which is an inhibitor of pain perception and acts by potentiating endogenous μ- and δ-opioid receptor-dependent enkephalinergic pathways. Here we demonstrate the functional specificity in vivo of human Opiorphin. The pain-suppressive potency of Opiorphin is as effective as morphine in the behavioral rat model of acute mechanical pain, the pin-pain test. Thus, our discovery of Opiorphin is extremely exciting from a physiological point of view in the context of endogenous opioidergic pathways, notably in modulating mood-related states and pain sensation. Furthermore, because of its in vivo properties, Opiorphin may have therapeutic implications.

Footnotes

^§To whom correspondence should be addressed. E-mail: crougeot{at}pasteur.fr
Author contributions: C.R. designed research; A.W., E.D., M.M., A.N., A.M., and C.R. performed research; A.W., M.M., A.M., and M.-N.U. contributed new reagents/analytic tools; A.W., E.D., M.M., A.N., A.M., and C.R. analyzed data; and C.R. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
Abbreviations:

SP,

substance P;

NEP,

neutral endopeptidase;

hNEP,

human NEP;

AP-N,

aminopeptidase N;

hAP-N,

human AP-N;

pAP-M,

porcine aminopeptidase M;

CE-HPLC,

cation-exchange HPLC;

SELDI-TOF MS,

surface-enhanced laser desorption ionization–time of flight mass spectrometry;

DPPIV,

dipeptidylpeptidase IV;

hDPPIV,

human DPPIV;

Ala-pNA,

l-alanine-p-nitoanilide.