Pharmacology of Neuro-Endocrine Regulations

  HEADDr ROUGEOT Catherine /

  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 recently discovered using a functional biochemical approach. Their structure/function elucidation was the result of physio-pharmacochemical studies.

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

The membrane-anchored NEP (Neutral ecto-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 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, 100; Messaoudi et al. Horm. & Behav., 2004, 46; Davies et al. British. J. Urol. Int., Oct 2006).

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-peptidase whose activity is related to the rat Sialorphin. We named it Opiorphin. We found that it prevented the Met-enkephalin breakdown mediated by the two enkephalin-inactivating ectopeptidases, AP-M aminopeptidase and hNEP. In vivo, Opiorphin displays potent analgesic activity at 1 mg/kg dose in chemical and mechanical (Pin-pain, Figure) 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; 103) (International Patent: 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, the program is 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.



Publications 2006 of the unit on Pasteur's references database

Activity Reports 2006 - Institut Pasteur
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