title: Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways.
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 mu- 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.
authors.affiliation: Laboratoire de Pharmacologie des Regulations Neuroendocrines, Institut Pasteur, 28 Rue du Docteur Roux, F-75724 Paris Cedex 15, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Wisner
authors.forename: Evelyne
authors.initials: E
authors.lastname: Dufour
authors.forename: Michaël
authors.initials: M
authors.lastname: Messaoudi
authors.forename: Amine
authors.initials: A
authors.lastname: Nejdi
authors.forename: Audrey
authors.initials: A
authors.lastname: Marcel
authors.forename: Marie-Noelle
authors.initials: MN
authors.lastname: Ungeheuer
authors.forename: Catherine
authors.initials: C
authors.lastname: Rougeot
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000700:Analgesics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D018826:CD13 Antigens / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism*; D018847:Opioid Peptides / Q000235:genetics / Q000378:metabolism*; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012463:Saliva / Q000737:chemistry; D012471:Salivary Proteins and Peptides / Q000235:genetics / Q000378:metabolism*
chemical_list: D000700:Analgesics; D004745:Enkephalins; D006023:Glycoproteins; D009842:Oligopeptides; D018847:Opioid Peptides; D011994:Recombinant Proteins; D012471:Salivary Proteins and Peptides; C517879:glutaminyl-arginyl-phenylalanyl-seryl-arginine; D018826:CD13 Antigens; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D015260:Neprilysin; D000243:Adenosine Deaminase