Dexmedetomidine alleviates anxiety-like behavior in mice following peripheral nerve injury by reducing thehyperactivity of glutamatergic neurons in the anterior cingulate cortex.

BACKGROUND

Treatment of chronic pain is challenged by concurrent anxiety symptoms. Dexmedetomidine is known to produce sedation, analgesia, and anxiolysis. However, the neural mechanism of dexmedetomidine-elicited anxiolysis remains elusive. Here, we aimed to test the hypothesis that the anterior cingulate cortex might be involved in dexmedetomidine-induced anxiolysis in pain.

METHODS

A common peroneal nerve ligation mouse model was used to test the dexmedetomidine-induced analgesia and anxiolysis by assessing mechanical allodynia, open-field, light-dark transition, and acoustic startle reflex tests. In vivo calcium signal fiber photometry and ex vivo whole-cell patch-clamp recordings were used to measure the excitability of glutamatergic neurons in anterior cingulate cortex. Modulation of glutamatergic neurons was performed by chemogenetic inhibition or activation via viral injection.

RESULTS

Compared with vehicle, dexmedetomidine (4 µg/kg) alleviated mechanical allodynia (P < 0.001) and anxiety-like behaviors (P < 0.001). The glutamatergic neurons' excitability after dexmedetomidine administration was lower than that of the vehicle group (P = 0.001). Anxiety-like behaviors were rescued by inhibiting glutamatergic neurons in the model mice. Nociception-related anxiety-like behavior was induced by activation of glutamatergic neurons, which was rescued by dexmedetomidine.

CONCLUSIONS

The reduction in glutamatergic neuronal activity in anterior cingulate cortex may be involved in dexmedetomidine-elicited anxiolysis in chronic pain.