LAUSR

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. Description Boosting endogenous opioid signaling Angiotensin-converting enzyme (ACE) is expressed in brain tissue, but the central function of ACE in the brain has proven enigmatic. Trieu et al. discovered that ACE has a noncanonical role in governing endogenous opioid signaling in the brain. ACE cleaves and degrades an unconventional enkephalin called Met-enkephalin-Arg-Phe (MERF). Unlike conventional enkephalin pentapeptides, MERF is selectively degraded by ACE and enhances μ-opioid receptor activation in the nucleus accumbens, perhaps explaining its antidepressant effects in patients taking ACE inhibitors. —PRS A pathway that controls signaling through the brain’s own opioids and that can be targeted to fine-tune neural circuit function is identified.