Can Blocking Angiotensin-Converting Enzyme Type 2 Impair Behaviour and Nociception in Healthy Mice?

The renin-angiotensin system (RAS) is an important regulator of functions in various systems, including the brain. A classic pathophysiological consequence of RAS imbalance is hypertension, but the system is also involved in the control of behaviour and the development of neurodegenerative diseases and psychiatric disorders. Angiotensin-converting enzyme type 2 (ACE2) is an important member of the protective arm of the RAS. We hypothesized that ACE2 blockade may alter the systemic balance controlling brain functions. The present study aimed to characterize the effect of systemic acute ACE2 blockade on some behavioural parameters and nociception in mice. Experiments were performed on male ICR mice treated acutely with the selective ACE2 inhibitor MLN-4760. We used a battery of behavioural tests: the “Elevated Plus Maze” for anxiety behaviour, the “Open Field” for exploratory behaviour, the “Hot Plate”, and formalin tests for thermal and chemical nociception, respectively. The results showed that acute treatment with the ACE2 inhibitor MLN reduces normal anxiety-like behaviour in a novel environment, as expressed by increased time spent in the open arms of the Elevated Plus Maze and increased distance in the central area of the Open Field Test. Short-term blockade of ACE2 produced antinociception in the acute thermal test and the inflammatory second phase of the formalin test. In summary, we can conclude that ACE2 is involved in the regulation of complex brain functions, such as motivational behaviour and pain perception.