Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity
| Autor: | Catherine Rougeot, Thierry Blisnick, Anne Gaëlle Rigault, Christophe Dugave, François Rougeon, Didier Desor, Véronique Hermitte, Michaël Messaoudi |
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| Přispěvatelé: | Génétique et Biochimie du Développement, Institut Pasteur [Paris], ETAP-Applied Ethology, Partenaires INRAE, Biologie des Interactions Hôte-Parasite, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Département d'Ingenierie et d'Etudes des Protéines (DIEP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Henri Poincaré - Nancy 1 (UHP), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2003 |
| Předmět: |
Male
MESH: Protein Precursors MESH: Analgesics MESH: Substance P Receptors Opioid mu Endogeny Substance P MESH: Amino Acid Sequence MESH: Pain Measurement Kidney MESH: Formaldehyde MESH: Spinal Cord chemistry.chemical_compound 0302 clinical medicine Receptors Opioid delta MESH: Receptors Opioid delta MESH: Animals MESH: Submandibular Gland Receptor Neprilysin Pain Measurement Endogenous opioid Analgesics 0303 health sciences Multidisciplinary MESH: Protease Inhibitors Chemistry MESH: Neprilysin Glycopeptides Prostate MESH: Salivary Proteins and Peptides Biological Sciences MESH: Enkephalin Methionine [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences Naltrexone 3. Good health Spinal Cord MESH: Naltrexone MESH: Pain MESH: Membrane Proteins medicine.drug Thiorphan medicine.medical_specialty MESH: Rats Enkephalin Methionine Molecular Sequence Data Submandibular Gland Pain MESH: Receptors Opioid mu MESH: Prostate 03 medical and health sciences Leucine In vivo Formaldehyde Internal medicine medicine Animals Protease Inhibitors Amino Acid Sequence Protein Precursors Rats Wistar Salivary Proteins and Peptides 030304 developmental biology MESH: Glycopeptides MESH: Molecular Sequence Data Opiorphin Membrane Proteins MESH: Thiorphan MESH: Rats Wistar MESH: Kidney In vitro MESH: Male Rats Endocrinology MESH: Leucine MESH: Wounds and Injuries Wounds and Injuries 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2003, 100 (14), pp.8549-8554. ⟨10.1073/pnas.1431850100⟩ Proceedings of the National Academy of Sciences of the United States of America, 2003, 100 (14), pp.8549-8554. ⟨10.1073/pnas.1431850100⟩ |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.1073/pnas.1431850100⟩ |
| Popis: | Sialorphin is an exocrine and endocrine signaling mediator, which has been identified by a genomic approach. It is synthesized predominantly in the submandibular gland and prostate of adult rats in response to androgen steroids and is released locally and systemically in response to stress. We now demonstrate that the cell surface molecule to which sialorphin binds in vivo in the rat kidney is the membrane-anchored neutral endopeptidase (neprilysin; NEP, EC 3.4.24.11). NEP plays an important role in nervous and peripheral tissues, as it turns off several peptide-signaling events at the cell surface. We show that sialorphin prevents spinal and renal NEP from breaking down its two physiologically relevant substrates, substance P and Met-enkephalin in vitro . Sialorphin inhibited the breakdown of substance P with an IC 50 of 0.4–1 μM and behaved as a competitive inhibitor. In vivo , i.v. sialorphin elicited potent antinociceptive responses in two behavioral rat models of injury-induced acute and tonic pain, the pin-pain test and formalin test. The analgesia induced by 100–200 μg/kg doses of sialorphin required the activation of μ- and δ-opioid receptors, consistent with the involvement of endogenous opioid receptors in enkephalinergic transmission. We conclude that sialorphin protects endogenous enkephalins released after nociceptive stimuli by inhibiting NEP in vivo . Sialorphin is a natural systemically active regulator of NEP activity. Furthermore, our study provides evidence that it is a physiological modulator of pain perception after injury and might be the progenitor of a new class of therapeutic molecules. |
| Databáze: | OpenAIRE |
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