Stress influences brain enkephalinase, oxytocinase and angiotensinase activities: a new hypothesis

Neuropsychobiology. 2009;59(3):184-9. doi: 10.1159/000219306. Epub 2009 May 20.


Brain enkephalin and oxytocin are anxiolytic agents involved in the response mechanism to stress. Degrading enzymes such as enkephalinase and oxytocinase could also be associated with this response. The effect of acute immobilization stress on enkephalinase and oxytocinase activities was determined in the soluble and membrane fractions of the medial prefrontal cortex, hippocampus and amygdala using alanyl- and leucyl-beta-naphthylamide as substrates, the latter in the presence and absence of 20 mM L-methionine. No change in aminopeptidase activities was observed in the prefrontal cortex of stressed rats. In contrast, enkephalinase activity decreased in the soluble fraction of the hippocampus but increased in the membrane fraction. In the amygdala, soluble oxytocinase and membrane enkephalinase activities decreased in stressed animals. These results show that acute immobilization stress affects differentially enkephalinase and oxytocinase activities depending on the fraction and brain region analyzed. A reduction in the activity of soluble enkephalinase in the hippocampus and soluble oxytocinase as well as membrane enkephalinase in the amygdala may suggest higher availability/longer action of enkephalin and oxytocin at these locations. This may explain the relative importance of these enzymatic activities in the anxiolytic properties proposed for enkephalins and oxytocin in the hippocampus and amygdala during stress conditions. This interpretation is not applicable to membrane enkephalinase activity in the hippocampus. However, alanyl-beta-naphthylamide hydrolyzing activity not only measures enkephalinase activity, it also reflects the angiotensinase-induced metabolism of angiotensin III to angiotensin IV. Therefore, our results may also mirror an increase in the formation of Ang IV in hippocampus and a decrease in the amygdala in acute stress. In conclusion, aminopeptidase activities in the hippocampus and amygdala may affect enkephalin, oxytocin and angiotensin III metabolism during acute immobilization stress and therefore be involved in the anxiolytic response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / enzymology
  • Analysis of Variance
  • Angiotensin II / metabolism
  • Angiotensin III / metabolism
  • Animals
  • Brain / enzymology*
  • Cell Membrane / metabolism
  • Cystinyl Aminopeptidase / metabolism*
  • Endopeptidases / metabolism*
  • Fluorometry
  • Hippocampus / enzymology
  • Male
  • Neprilysin / metabolism*
  • Prefrontal Cortex / enzymology
  • Rats
  • Rats, Wistar
  • Restraint, Physical
  • Stress, Psychological / enzymology*


  • angiotensinase
  • Angiotensin II
  • Angiotensin III
  • Endopeptidases
  • Cystinyl Aminopeptidase
  • Neprilysin