Key result
Central ACE inhibition in mice enhanced endogenous opioid signaling, decreased fentanyl-induced conditioned place preference, and enhanced reciprocal social interaction.
Why the study?
In the brain, ACE is expressed at uniquely high levels in the striatonigral pathway, but its central function remains poorly understood.
Does systemic ACE inhibition enhance endogenous opioid signaling and alter addiction-related behaviors in mice?
Does systemic ACE inhibition enhance endogenous opioid signaling and alter addiction-related behaviors in mice?
Central ACE inhibition boosts endogenous opioid signaling, which may offer clinical benefits such as mitigating the risk of addiction and enhancing social interaction.
Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is expressed at uniquely high levels in the striatonigral pathway, but its central function remains poorly understood. We find that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe, in the nucleus accumbens of mice. ACE inhibition enhanced mu 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 decreased the conditioned place preference caused by fentanyl administration, and enhanced reciprocal social interaction. Our results raise the enticing prospect that central ACE inhibition can boost endogenous opioid signaling for clinical benefit, while mitigating risk of addiction.
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Trieu et al. (2021) studied Opioid signaling and addiction. ACE inhibition was evaluated on Mu opioid receptor activation, glutamate release, conditioned place preference, and social interaction. Central ACE inhibition in mice enhanced endogenous opioid signaling, decreased fentanyl-induced conditioned place preference, and enhanced reciprocal social interaction.
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