Angiotensin-converting enzyme gates brain circuit-specific plasticity via an endogenous opioid

Science. 2022 Mar 11;375(6585):1177-1182. doi: 10.1126/science.abl5130. Epub 2022 Feb 24.


Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is especially abundant in striatal tissue, but the function of ACE in striatal circuits remains poorly understood. We found that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe, in the nucleus accumbens of mice. ACE inhibition enhanced µ-opioid receptor activation by Met-enkephalin-Arg-Phe, causing a cell type-specific long-term depression of glutamate release onto medium spiny projection neurons expressing the Drd1 dopamine receptor. Systemic ACE inhibition was not intrinsically rewarding, but it led to a decrease in conditioned place preference caused by fentanyl administration and an enhancement of reciprocal social interaction. Our results raise the enticing prospect that central ACE inhibition can boost endogenous opioid signaling for clinical benefit while mitigating the risk of addiction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Animals
  • Behavior, Animal / drug effects
  • Captopril / pharmacology
  • Enkephalin, Methionine / analogs & derivatives*
  • Enkephalin, Methionine / metabolism
  • Female
  • Fentanyl / pharmacology
  • Male
  • Mice
  • Miniature Postsynaptic Potentials
  • Neuronal Plasticity*
  • Nucleus Accumbens / metabolism*
  • Opioid Peptides / metabolism
  • Patch-Clamp Techniques
  • Peptidyl-Dipeptidase A / metabolism*


  • Angiotensin-Converting Enzyme Inhibitors
  • Opioid Peptides
  • Enkephalin, Methionine
  • enkephalin-Met, Arg(6)-Phe(7)-
  • Captopril
  • Peptidyl-Dipeptidase A
  • Fentanyl