Neutral endopeptidase knockout induces hyperalgesia in a model of visceral pain, an effect related to bradykinin and nitric oxide

Hanspeter S. Fischer, Gerald Zernig, Kurt F. Hauser, Craig Gerard, Louis B. Hersh, Alois Saria

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Neutral endopeptidase (EC3.4.24.11, NEP, enkephalinase) is a zinc-metalloendopeptidase, cleaving a variety of substrates like enkephalins, substance P, and bradykinin. In the brain, NEP is a key enzyme in the degradation of enkephalins. Pharmacological inhibition of NEP-activity causes analgesia resulting from enhanced extracellular enkephalin concentrations. Recently, transgenic mice lacking the enzyme NEP have been developed (Lu, 1995). The present study was designed to investigate the nociceptive behavior of these NEP-knockout mice. Interestingly, NEP-deficient mice did not respond with decreased pain perception, but exhibited hyperalgesia in the hot-plate jump, warm-water tail-withdrawal, and most notably in the acetic-acid writhing test. Inhibition of aminopeptidase N by bestatin reduced writhing in both strains, whereas NEP-inhibition by thiorphan reduced writhing selectively in wild-type mice. Naloxone increased writhing in wild-type but not in knockouts, whereas the bradykinin B2-receptor antagonist HOE140 reduced writhing selectively in NEP-knockouts. Similarly, the nitric oxide synthase inhibitor L-NAME reduced writhing in NEP-knockouts. These results indicate that genetic elimination of NEP, in contrast to pharmacological inhibition, leads to bradykinin-induced hyperalgesia instead of enkephalin-mediated analgesia. Nitric oxide (NO) is suggested to be involved in this process.

Original languageEnglish
Pages (from-to)129-134
Number of pages6
JournalJournal of Molecular Neuroscience
Issue number1-2
StatePublished - 2002

Bibliographical note

Funding Information:
This study was supported by the Austrian science fund #F00206, and the Austrian National Bank Jubilee Funds (grant no. 6564). The technical help of Mrs. Astrid Saria and Mrs. Margit Auffinger is gratefully acknowledged.


  • Bradykinin
  • Enkephalins
  • Knockout mice, enkephalinase
  • Neutral endopeptidase
  • Nociception

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience


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