Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity

Abstract

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 IC50 of 0.4 -1 M 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 g͞kg doses of sialorphin required the activation of -and ␦-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.

Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways

“…Our data provide direct evidence for the existence of a natural inhibitor of the cell-surface hNEP peptidase, a QRFSR pentapeptide, which is secreted into the human saliva and whose activity is related to the rat sialorphin QHNPR pentapeptide (13) and bovine spinorphin LVVYPWT heptapeptide (7); we named it Opiorphin. Furthermore, it appears that Opiorphin corresponds to the putative mature product of the PRL1 precursor (16).…”

“…It is a physiological inhibitor of the membrane-anchored rat NEP activity and is a powerful inhibitor of pain sensation in rats (9)(10)(11)(12)(13). To our knowledge, bovine spinorphin and rat sialorphin are the only identified natural enkephalin catabolism inhibitors inducing antinociception in mammals (8,13). We therefore asked whether this important inhibitor also is present in humans.…”

Noxious mechanical stimulation evokes the segmental release of opioid peptides that induce μ-opioid receptor internalization in the presence of peptidase inhibitors

“…The most likely explanation for this paradox is that there are endogenous peptidase inhibitors that enable the action of opioids. In fact, three endogenous inhibitors of aminopeptidase and neutral endopeptidase have been found: spinorphin -LVVYPWT (Nishimura and Hazato, 1993), sialorphin -QHNPR (Rougeot et al, 2003) and opiorphin -QRFSR (Wisner et al, 2006). The release of these peptidase-inhibiting peptides appears to play a role in pain control, since sialorphin and opiorphin have analgesic properties, while spinorphin increased the antinociception produced by Leu-enkephalin (Honda et al, 2001).…”

hSMR3A as a Marker for Patients With Erectile Dysfunction

“…10 Sialorphin acts as an inhibitor of rat membrane bound NEP. 15 We proposed that the ability of sialorphin to prolong the activity of agonists that are normally broken down by NEPs causes heightened smooth muscle relaxation in the corpora cavernosa, leading to penile erection. Given the similarity of the amino acid sequence and the fact that SMR3A and Vcsa1 are down-regulated with ED, it is likely that hSMR3A also gives rise to peptide products that act as NEP inhibitors and, thereby, cause human corporeal smooth muscle tissue relaxation.…”