The anxiolytic mechanism of dexmedetomidine may provide an important theoretical basis and target fo

On February 18, 2024, Prof. Xuesheng Liu's group in the Department of Anesthesiology, the First Affiliated Hospital of Anhui Medical University published a paper entitled "Dexmedetomidine inhibits paraventricular corticotropin- releasing hormone neurons that attenuate acute stress-induced anxiety-like behavior in mice" in Anesthesiology, a leading anesthesia journal, releasing hormone neurons that attenuate acute stress-induced anxiety-like behavior in mice".

Anxiety disorders are common clinical mental disorders, surgical trauma is one of the important triggers, and its main manifestation is intense and excessive fear and worry. Since the central nervous mechanism of anxiety disorders has not yet been studied clearly, its prevention and treatment are unsatisfactory. Several clinical studies have shown that the anesthetic drug dexmedetomidine can improve anxiety in perioperative patients, however, the specific neural mechanism of dexmedetomidine's anxiolytic properties is not known. Unraveling the anxiolytic mechanism of dexmedetomidine may provide an important theoretical basis and target for the treatment of anxiety disorders.

In this published study, the group first validated the anxiolytic effects of dexmedetomidine in mice. The authors used the classical social defeat test (SDS) to model anxiety and found that, compared with the control group, SDS mice had significantly reduced the percentage of entries and retention times in the open arm of the elevated cross maze, as well as significantly reduced the number of entries and retention times in the central area of the open field, and had increased peripheral blood levels of stress-related hormones. This result indicated that the SDS rat anxiety model was successfully modeled. The intraperitoneal injection of dexmedetomidine improved the anxiety-like behavior of mice in the elevated cross maze and open field experiments, and the anxiety hormone levels of mice were reduced.

Next, the authors explored the central mechanisms underlying the anxiolytic effects of dexmedetomidine. Given that PVN CRH neurons are important brain regions that mediate and integrate the effects of stress stress, the authors used fiber optic recordings to observe calcium activity in PVN CRH neurons. It was found that the activity of PVN CRH neurons increased during SDS and lasted for at least 3 hours. Meanwhile, the authors further verified this finding by techniques such as isolated membrane clamp and c-Fos staining, and the above results indicated that PVN CRH neurons were activated in the SDS anxiety model. Then, the authors further found that dexmedetomidine effectively inhibited PVN CRH neurons using fiber-optic recordings, isolated membrane-clamp recordings, and that the inhibitory effect of dexmedetomidine on PVN CRH neurons disappeared in acute brain slices after administration of yohimbine, an α2 receptor antagonist. This suggests that dexmedetomidine can inhibit neuronal activity by activating α2 receptors on PVN CRH neurons. Finally, to determine the important role of PVN CRH neurons in dexmedetomidine anxiolysis. The researchers used chemical genetics to activate/inhibit PVN CRH neurons to study their effects on the anxiolytic effects of dexmedetomidine. The results showed that activation of PVN CRH neurons significantly reduced the percentage of entries and the percentage of retention time in the open arm of the elevated cross maze in mice; the same was true for the number of entries and retention time in the center region of the open field. The complete opposite was true for inhibition of PVN CRH neurons. In conclusion, dexmedetomidine exerts its anxiolytic effects by inhibiting PVN CRH neurons.

This study reveals the potential mechanism by which dexmedetomidine alleviates stress-induced anxiety: dexmedetomidine exerts its anxiolytic effect by activating α2 receptors on PVN CRH neurons and inhibiting PVN CRH neuronal activity.