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

Wisner A, Dufour E, Messaoudi M, Nejdi A, Marcel A, Ungeheuer MN, Rougeot C.
Laboratoire de Pharmacologie des Regulations Neuroendocrines,
Institut Pasteur, 28 Rue du Docteur Roux,
F-75724 Paris Cedex 15, France;
ETAP-Ethologie Appliquee, 13 Rue du Bois de la Champelle,
F-54500 Vandoeuvre-les-Nancy, France.
Proc Natl Acad Sci U S A. 2006 Nov 13;


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, and human ecto-aminopeptidase, hAP-N (EC 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 micro- and delta-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.
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