Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways.
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.
Wisner
Anne
A
Laboratoire de Pharmacologie des Regulations Neuroendocrines, Institut Pasteur, 28 Rue du Docteur Roux, F-75724 Paris Cedex 15, France.
Dufour
Evelyne
E
Messaoudi
Michaël
M
Nejdi
Amine
A
Marcel
Audrey
A
Ungeheuer
Marie-Noelle
MN
Rougeot
Catherine
C
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*
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