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  Director : Rougeot Catherine (crougeot@pasteur.fr)


  abstract

 

Research program of the laboratory is focused on the exploration of the physiological activities of the first endogenous regulator of membrane-anchored NeutralEndoPeptidase (NEP-Enkephalinase) activities, identified to date in rat and named sialorphin, and on the molecular characterization of its mimetic derivatives, including the functional sialorphin-homologous endogenous NEP-inhibitor, in human.



  report

cale

Molecular and functional characterization of metallo-ectopeptidase natural antagonists, in rodent and human species.

In a physiomic approach, we have established the molecular bases providing the existence of an endogenous regulator of membrane-anchored NeutralEndoPeptidase (NEP-Enkephalinase) activities in mammals. From an integrative point of view, the combined physiological and genomic information accrued from 1992 to 2002, led us to suggest that in rat, the physiological peptide-mediator named sialorphin, is involved in the tonic and dynamic coordination of components of the integrative behavioral response of the organism to an aggression. Thus, on one hand, this specific exocrine and endocrine signal messenger is mobilized in vivo under neuroendocrine control and, more particularly upon urgent situations. And, on the other hand, we have showed that the circulating sialorphin is a physiological antagonist of a membrane metalloecto-endopeptidase activity, the NEP, which catalyzes the post-secretory metabolism of neuroendocrine peptides controlling (i) the cardiovascular and inflammatory (Substance P, Bradykinin) responses, (ii) the nociceptive (Enkephalins) response and (iii) the phosphate and sodium homeostatic exchanges (Atrial/Brain/C-type Natriuretic Peptides, ANP, BNP, CNP).

By using various models of molecular pharmacology and behavioral pharmacology, we showed that sialorphin:

- In vitro, shares the kinetic behavioral characteristic of a competitive inhibitor of the rat cell surface-bound NEP, that this one derived from nervous tissues (spinal cord) or from peripheral systemic target tissues for sialorphin, in vivo (kidney, bone, tooth) (photo).

- In vivo, displays analgesic activity in various behavioral rat models of injury-induced acute and tonic pain (peripheral, spinal and supraspinal). The analgesia induced by sialorphin required the activation of µ- and ?-opioid receptors, consistent with the involvement of endogenous opioid receptors in enkephalinergic transmission. Indeed, ?- and µ- opioid receptors are involved in the transmission of opioidergic endogenous signals (enkephalins) and of the opiate alkaloid exogenous agonist (morphine). We conclude that the sialorphin protects endogenous enkephalins released following nociceptive stimuli by inhibiting inactivating enkephalinase, in vivo (Rougeot and al., submitted manuscript).

Sialorphin is the first natural systemically active regulator of NEP activity identified to date. Furthermore, our study provides evidence that it is a new physiological modulator of pain perception following injury, and may be the progenitor of a new class of therapeutic compound for pain management.

The future conceptual and experimental approaches will consist in identifying all the molecular, cellular and integrative mechanisms involved in the interaction of sialorphin with NEP or with the other members of the mammalian integral plasma membrane metallo-endopeptidase family, in rodent and in human species. So, we shall establish all the biochemical and physio-pharmacological parameters governing this interaction and its physiological consequences at the cell level (established cell lines and/or transfected cells with the various ectopeptidase-cDNAs) as well as at the level of whole body (rodents and primates models).

Legend: Representative macro- and micro-autoradiographic images of the biodistribution of systemic target organs and tissues for radio-labeled sialorphin (3H), in vivo, in male rat: Analyses by using quantitative auto radiographic Beta- and Micro-Imagers (collaboration with Ana Cardona, URE en Histotechnologie et Pathology).Red color represents the highest radioactive signal.

Keywords: Pharmacology, Pain, Stress, Peptide hormone mediator, Metallo-ectopeptidases, Enkephalins



  publications

puce Publications of the unit on Pasteur's references database


  personnel

  Office staff Researchers Scientific trainees Other personnel
    Rougeot, Catherine, Institut Pasteur, (chef de laboratoire,crougeot@pasteur.fr) Desclaux, Mathieu, Etudiant DEA “Biologie et Productions animales” (ENSAR/U. Rennes1) Wisner, Anne, (Ingénieur de recherché Institut Pasteur,awisner@pasteur.fr)

Dufour, Evelyne, (Technicien Supérieur Institut Pasteur,edufour@pasteur.fr)

Activity Reports 2002 - Institut Pasteur
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