Pharmacology of Neuro-Endocrine Regulations  

  HEADDr. Rougeot Catherine /
  MEMBERSDr. Robert Fabienne / Dr. Villard-Saussine Sylvie / Evelyne Dufour (technicien supérieur) / Marjorie Lebarbenchon (étudiant M1: Licence Professionnelle des Biotechnologies)

  Annual Report

THE DISCOVERY OF RAT SIALORPHIN AND HUMAN OPIORPHIN: new modulators of opioid-dependent pathways

Sialorphin was identified using an integrative post-genomic approach and Opiorphin was discovered using a functional biochemical approach. Their structure/function elucidation was the result of integrative pharmaco-chemical studies.

Rat Sialorphin, the first natural regulator of NEP-enkephalinase activity, identified in mammals

The membrane-anchored NEP (Neutral EndoPeptidase) plays a dynamic role in controlling the activity of enkephalins, the opioid neuropeptides, which are involved in the modulation of behavioral adaptive responses to stressful environmental stimuli. Opioid pathways notably regulate spinal processing of nociceptive information and analgesic mechanisms, emotional and/or motivational responses. We first characterized Sialorphin in rats, a new peptide mediator involved in adaptation to environmental changes. We determined its functional specificity in vivo, as a physiological ligand and competitive inhibitor of rat NEP, as a potent inhibitor of painful sensation and a physiological modulator of environmental and socio-sexual motivation in male rats (Rougeot et al. PNAS, 2003; Messaoudi et al. Horm.&Behav., 2004; Davies et al. British. J. Urol. Int., 2007).

Human Opiorphin, a novel anti-nociceptive modulator of opioid-dependent pathways.

Using a functional biochemical approach, we isolated in Human an inhibitor of the cell surface hNEP-ectopeptidase whose activity is related to the rat Sialorphin. We named it Opiorphin (Figure: In silico representive image of Opiorphin 2D structure). Owing to the complementary role of cell surface NEP and AP-N (AminoPeptidase-N) in enkephalin inactivation, we found that Opiorphin prevented in a concentration-dependent manner the Met-enkephalin breakdown mediated by the two ectopeptidases. In vivo, Opiorphin displays potent analgesic activity at 1 mg/kg dose in chemical and mechanical pain rat models by activating endogenous opioid-dependent transmission. Its pain-suppressive effect is as efficient as morphine whose activity depends on µ-opioid receptors.

We proposed that the analgesic effect of Opiorphin is due to inhibition of the two enkephalin-inactivating ectopeptidases, NEP and AP-N, in vivo allowing protection of the endogenous enkephalins released after pain stimuli and potentiation of enkephalin-mediated anti-nociception. (Wisner et al. PNAS, Nov 2006) (International Patent: Rougeot et al. WO2005/090386).

Our discovery is of interest from a physiological point of view, in the context of endogenous opioid pathways, notably in modulating mood-related states and pain sensation. And, because of its in vivo properties, Opiorphin may have therapeutic implications. Thus, programs are currently in a way to study its pharmacological profile in depth and its secretion pattern in Human as well as to make conformationally restricted Opiorphin mimetics with appropriate pharmacokinetic and biodistribution properties as new anti-pain drug-candidates.

Keywords: Biochemistry – Bioactive Peptides – Pharmacology – Pain Syndromes – Emotional Disorders



Kelvin P. Davies, M. Tar, C. Rougeot, A. Melman Feb 2007) Sialorphin (The Mature Peptide Product of Vcsa1) Relaxes Corporal Smooth Muscle Tissue and Increases Erectile Function in the Aging Rat. British J. of Urol. Int.,99(2): 431-435. PMID 17026587

F. Medja, R. H. Fontaine, F. Lebas, P. Leroux, A. Saria, C. Rougeot,P. Dournaud, V. Lelièvre, P. Gressens (Dec 2006) Thiorphan, a neutral endopeptidase (NEP) inhibitor used for diarrhea, is neuroprotective in newborn mice; BRAIN, 129(12): 3209-3223. PMID 17028311

A. Wisner, E. Dufour, M. Messaoudi,A. Nejdi, A. Marcel, M.N. Ungeheuer, C. Rougeot(Nov 2006)Human Opiorphin, a Novel Anti-nociceptive Modulator of Opioid-Dependent Pathways; Proc. Natl. Acad. Sci. USA,103(47):17979-17984. PMID 17101991

M. Messaoudi , D. Desor, A. Nejdi, and C. Rougeot (2004) The endogenous androgen-regulated sialorphin modulates male rat sexual behavior. Hormones & Behavior. 46(5): 684-691. PMID 15555512

C. Rougeot, M. Messaoudi, V. Hermitte, A.G. Rigault, T. Blisnick , C. Dugave, D. Desor, and F. Rougeon(Jul2003) Sialorphin, a natural inhibitor of membrane-bound neutral endopeptidase that displays analgesic activity. Proc. Natl. Acad. Sci. USA, 100 (14): 8549-8554. PMID 12835417

Activity Reports 2007 - Institut Pasteur
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