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     Pharmacology of Neuro-Endocrine Regulations


  Director : Rougeot Catherine (crougeot@pasteur.fr)


  abstract

 

Research of the laboratory is focused on the molecular characterization and in vivo functional exploration of the endogenous inhibitors of membrane-anchored metallo-ectopeptidases, which are involved in the regulation of crucial physiological functions in mammals, especially in that of pain perception.



  report

cale

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

In a physiomic approach, we have established the molecular and functional bases providing the existence of an endogenous regulator of metalloecto-peptidase activity in mammals. Hence, we characterized the peptide-mediator sialorphin, which is the first physiological inhibitor of membrane NEP (Neutral EndoPeptidase) or Enkephalinase activity identified to date in rodent; this endocrine signal messenger of the adaptative response to stress is a powerful inhibitor of painful perception in rat and its analgesic effect is more potent than that of synthetic inhibitors which have been developed elsewhere by modeling methods.

For instance, analyses of molecular pharmacology and behavioral pharmacology have revealed that sialorphin:

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

- In vivo, displays potent analgesic activity in two behavioral rat models of injury-induced acute and tonic pain. The analgesia induced by sialorphin required the activation of mu- and delta- opioid receptors, consistent with the involvement of endogenous opioid receptors in enkephalinergic transmission. Indeed, these receptors are involved in the transmission of endogenous opiate signals, such as the enkephalins which are inactivated by both metallo-ectopeptidases, NEP and Aminopeptidase APN, and also of the exogenous opiate mu-agonist, morphine. Otherwise, in a behavioral despair model, sialorphin exerts anti-depressive activity in male rat whilst in a behavioral anxiety model it doesn't display anxiolytic effect (collaboration with M. Messaoudi, ETAP-applied ethology research centre, Nancy).

We conclude that the sialorphin protects endogenous enkephalins released following nociceptive stimuli by inhibiting inactivating enkephalinases, in vivo, and thus potentializing their anti-nociceptive and anti-depressive actions.

In mammals, the cell surface metallo-ectopeptidases as well as their physiological substrate-effector and inhibitor which are neuroendocrine peptide mediators, are responsible for the coordinated control of major biological functions such as cardiovascular, inflammatory and nociceptive functions as well as calcium, sodium and phosphate homeostatic exchanges. From a physiological as well as physiopathological and therapeutic point of view, the biological importance of the functions regulated by these peptide mediators makes it crucial to investigate and knowledge their inactivation mechanism and potential protection in vivo by endogenous inhibitors.

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 painful responses to threatening environments in rats, and may be the progenitor of a new class of therapeutic compound for pain management.

Legend: Representative macro- and micro-autoradiographic images of the biodistribution of systemic target organs tissues and cells for radio-labeled sialorphin (3H), in vivo, in male rat: Analyses by using quantitative autoradiographic Beta- and Micro-Imagers (visualization of target organs and tissues, respectively in red color, collaboration with Ana Cardona, URE en Histotechnologie et Pathology); and by micro-autoradiography (visualization of target cells represented by black silver grains).

Keywords: Pharmacology, Pain, Stress, Peptide hormone mediator, Opiate, Enkephalinase



  publications

puce Publications 2003 of the unit on Pasteur's references database


  personnel

  Office staff Researchers Scientific trainees Other personnel
    Rougeot, Catherine, Institut Pasteur, (crougeot@pasteur.fr) Marcel, Audrey, Etudiante DESS “Génie Cellulaire” (Nancy) Wisner, Anne, Ingénieur de recherché Institut Pasteur, awisner@pasteur.fr

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

Activity Reports 2003 - Institut Pasteur
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