Mice mortality induced by dexmedetomidine is non-alpha2-adrenergic receptor-dependent

Dexmedetomidine (DMED) is widely used in sedative anesthetics in clinical settings. Currently, there are no therapeutic interventions available for the lethal toxicity induced by DMED. Administered at doses ranging from 25 to 100 mg/kg intraperitoneally (i.p.), DMED exhibited a dose-dependent fatality in mice. The 50 % lethal dose (LD50) was determined to be 48.5 mg/kg within 24 h and 44.8 mg/kg within 7 days. Alpha2-adrenergic receptor antagonists, namely yohimbine and atipamezole, demonstrated no mitigating effect on the lethal toxicity induced by DMED at the dose of 44.8 mg/kg. Conversely, the administration of atipamezole and yohimbine increased the mortality associated with DMED. By contrast, the imidazoline receptor antagonist idazoxan and the opioid receptor antagonist naloxone significantly attenuated the mortality induced by DMED, thereby prolonging the median survival time following administration of DMED at 44.8 mg/kg (i.p.). Furthermore, the immune modulator imiquimod, calcium sensitizer levosimendan, and TAAR1 antagonist RO5212773 decreased acute mortality without impacting chronic mortality induced by DMED. Histopathological analysis revealed characteristic lung alterations, including capillary hemorrhage, widened alveolar septa, fusion of pulmonary alveoli, and inflammatory cell infiltrate upon DMED exposure. Pretreatment with idazoxan or naloxone inhibited these pathological changes induced by DMED, while atipamezole or yohimbine pretreatment exacerbated lung damage. Elevated levels of serum creatine kinase and myoglobin were noted following DMED administration. However, pretreatment with idazoxan or naloxone decreased the rise of serum creatine kinase and myoglobin. Collectively, these results highlighted the involvement of imidazoline receptors and opioid receptor in DMED mortality.