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

• Published in: Journal of molecular neuroscience 2002-02, Vol.18 (1-2), p.129-134
• Main Authors: Fischer, Hanspeter S, Zernig, Gerald, Hauser, Kurt F, Gerard, Craig, Hersh, Louis B, Saria, Alois
• Format: Article
• Language: English
• Subjects: Animals; Bradykinin - analogs & derivatives; Bradykinin - metabolism; Bradykinin - pharmacology; Captopril - pharmacology; Central Nervous System - drug effects; Central Nervous System - enzymology; Central Nervous System - physiopathology; Enkephalins - metabolism; Female; Hyperalgesia - enzymology; Hyperalgesia - genetics; Hyperalgesia - physiopathology; Leucine - analogs & derivatives; Leucine - pharmacology; Male; Mice; Mice, Knockout; Naloxone - pharmacology; Neprilysin - deficiency; Neprilysin - genetics; Neurons - drug effects; Neurons - enzymology; NG-Nitroarginine Methyl Ester - pharmacology; Nitric oxide; Nitric Oxide - metabolism; Pain - enzymology; Pain - genetics; Pain - physiopathology; Pain Measurement - drug effects; Piperidines - pharmacology; Quinuclidines - pharmacology; Reaction Time - drug effects; Reaction Time - physiology; Rodents; Thiorphan - pharmacology; Viscera - innervation; Visceral Afferents - drug effects; Visceral Afferents - enzymology; Visceral Afferents - physiopathology
• ISSN: 0895-8696; 0895-8696; 1559-1166
• DOI: 10.1385/JMN:18:1-2:129

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 mostnotablyin theacetic-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.