OPIOID-RELATED CHANGES IN NOCICEPTIVE THRESHOLD AND IN TISSUE-LEVELS OF ENKEPHALINS AFTER TARGET DISRUPTION OF THE GENE FOR NEUTRAL ENDOPEPTIDASE (EC-3.4.24.11) IN MICE

Neutral endopeptidase EC 3.4.24.11 (NEP) is localized in peptidergic n eurons and various colocalized peptides or other humoral mediators may serve as substrates. Target disruption of the NEP gene was reported t o enhance the lethal response to endotoxin shock in mice. We examined thermonociceptive thresholds and enkephalin (ENK) tissue levels in tra nsgenic NEP (-/-) and control wild type NEP (+/+) mice. Hot plate (52 degrees C) latency was 13.1 +/- 1.4 s in NEP (+/+) mice (n = 16) while latency increased significantly (P = 0.031) to 17.7 +/- 1.6 s in NEP (-/-) mice. Naloxone (10 mg/kg) had no effect on hot plate latency in NEP (+/+) mice (12.5 s, n = 8), but significantly decreased the latenc y in NEP (-/-) mice compared to untreated NEP (-/-) deficient mice (10 .5 s, n = 8); Morphine (3 or 10 mg/kg) analgesic response was similar in knockout mice and wild type mice. Methionine-ENK (MET-ENK) and leuc ine-ENK (LEU-ENK) levels were determined in extracts from cortex, brai n stem, hypothalamus, striatum, spinal cord, trigeminal ganglion and h eart in treated and untreated mice. ENK-levels varied in a regionally- dependent manner and were significantly decreased in hypothalamus and spinal cord. We conclude that deletion of the NEP gene results in an o pioid-related increase in thermonociceptive threshold. Regional differ ences in opioid metabolism indicate that NEP evokes tissue-specific pa tterns of ENK-regulation. NEP selectively controls opioid biosynthesis in hypothalamus and spinal cord presumably by feedback regulation. (C ) 1997 Elsevier Science Ireland Ltd.