Blocking a Specific Part of ACE Prevents the Brain from Breaking Down Natural Opioid Peptides

What the researchers found

Using brain slices from mutant mice with functional inactivation of either ACE catalytic domain, researchers demonstrated that only N-terminal domain inactivation reduced the degradation of Met-enkephalin-Arg-Phe (MERF) to Met-enkephalin. C-terminal domain inactivation had no effect. A selective N-terminal domain inhibitor (RXP 407) reduced degradation of both exogenously applied and endogenously released MERF, while leaving degradation of Met-enkephalin and Leu-enkephalin unaffected.

Why it matters

Current opioid medications work by flooding receptors with synthetic agonists, causing tolerance and addiction. Boosting the brain's own opioid peptides by preventing their breakdown could be safer. This study identifies a precise molecular target — the ACE N-terminal domain — that could enable this strategy.

The numbers in context

2 ACE catalytic domains studied; N-terminal domain identified as primary MERF degradation site; RXP 407 selective inhibitor tested; both sexes of mice used

How the study worked

Researchers used acute brain slice preparations from mice of both sexes, including mutant lines with functional inactivation of either the N-terminal or C-terminal ACE domain. Brain slices were incubated with exogenous MERF at saturating concentration and degradation was measured. A selective N-terminal domain inhibitor (RXP 407) was also tested on degradation of both exogenously applied and endogenously released enkephalin peptides.

Who was studied

Mouse brain tissue (both sexes), including mutant lines with domain-specific ACE inactivation

What this study cannot tell us

Preprint not yet peer-reviewed. Ex vivo brain slice study, not in vivo. No behavioral outcomes measured. Translation to human brain physiology unknown. Selective inhibitor tested only in tissue, not in living animals.

How to read the evidence

This is a mechanistic preclinical study using mouse brain slices and mutant mouse lines. The experimental design is rigorous with good controls, but it's a preprint (not yet peer-reviewed) and uses ex vivo tissue rather than in vivo models, placing it at moderate-preclinical evidence strength.

When this study was published

Published as a preprint in January 2025, this is very recent research. It has not yet been peer-reviewed, so findings should be interpreted with appropriate caution pending formal publication.

The bigger picture

This research sits at the intersection of two well-studied peptide systems: the angiotensin system (blood pressure) and the endogenous opioid system (pain and mood). By showing that a specific domain of ACE selectively degrades a specific opioid peptide in the brain, it opens a highly targeted pharmacological approach. Rather than the blunt instrument of opioid agonists, future drugs could fine-tune the brain's own opioid tone by modulating peptide degradation.

Questions still open

• Does N-terminal ACE inhibition produce analgesic or antidepressant effects in living animals?
• Could existing ACE inhibitors used for blood pressure have unrecognized effects on brain opioid signaling?
• Can domain-selective ACE inhibitors be designed to cross the blood-brain barrier for therapeutic use?

Common questions

Read the original research

Inhibition of the angiotensin-converting enzyme N-terminal catalytic domain prevents endogenous opioid degradation in brain tissue.

bioRxiv : the preprint server for biology

Citation

Hanak, Filip; Swanson, Jessica L; Felczak, Krzysztof; Bernstein, Kenneth E; More, Swati S; Rothwell, Patrick E. (2025). Inhibition of the angiotensin-converting enzyme N-terminal catalytic domain prevents endogenous opioid degradation in brain tissue.. bioRxiv : the preprint server for biology. https://doi.org/10.1101/2025.01.21.634163