Regulation of I1-imidazoline receptors on the sedation effect of dexmedetomidine in mice

Xiao Han; Zhi-Fang Yang; Tai-Yun Zhao; Guan-Yi Lu; Zhi-Yuan Wang; Ning Wu; Jin Li; Fei Li

doi:10.1007/s00210-024-02991-2

Regulation of I1-imidazoline receptors on the sedation effect of dexmedetomidine in mice

Naunyn Schmiedebergs Arch Pharmacol. 2024 Feb 16. doi: 10.1007/s00210-024-02991-2. Online ahead of print.

Authors

Xiao Han¹, Zhi-Fang Yang¹, Tai-Yun Zhao¹, Guan-Yi Lu¹, Zhi-Yuan Wang¹, Ning Wu¹, Jin Li², Fei Li³

Affiliations

¹ Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing, 100850, China.
² Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing, 100850, China. jinli9802@163.com.
³ Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing, 100850, China. lf5335317@163.com.

PMID: 38363351
DOI: 10.1007/s00210-024-02991-2

Abstract

Dexmedetomidine has been used as a sedative drug in the clinic for a long time. Many studies demonstrated that the sedative mechanism of dexmedetomidine might be related to the activation of α2-adrenoceptor (α2AR). In addition, it was reported that dexmedetomidine had some affinity for the I1-imidazoline receptor (I1R); however, the role of I1R in dexmedetomidine-induced sedative effects and its possible mechanism are poorly studied. In the present study, we found that agmatine, an I1R agonist, was able to enhance the sedative effect of dexmedetomidine in mice. Efaroxan, an α2AR and I1R antagonist, could prevent and rescue the sedative action of dexmedetomidine in mice, and its preventive effect was better than atipamezole, the specific α2AR antagonist. Knockout of imidazoline receptor antisera-selected (IRAS), the functional I1R candidate protein, suppressed the dexmedetomidine-induced sedation. Moreover, IRAS knockout led to the inhibition of agmatine and efaroxan in regulating dexmedetomidine-induced sedative effects in mice, but not of atipamezole. We then used CHO cell lines that stably expressed α2AR and IRAS to investigate the possible molecular mechanism of IRAS in regulating the dexmedetomidine-induced sedative effect. The results showed that IRAS expression significantly up-regulated dexmedetomidine-induced ERK phosphorylation, which was enhanced by agmatine and inhibited by efaroxan at low concentrations. Therefore, by taking advantage of pharmacological and genetic approaches, our finding revealed the evidence that IRAS plays an important role in the sedative effects of dexmedetomidine, and the ERK signal pathway may be involved in the mechanism of IRAS in regulating dexmedetomidine-induced sedation. This study may offer valuable insights for the advancement of novel anesthetic adjuvants.

Keywords: Anesthesia; Dexmedetomidine; I1-imidazoline receptor; Imidazoline receptor antisera-selected; α2-Adrenoceptor.