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Purpose <p>To investigate the role of brain noradrenergic and orexinergic activity in ketamine-induced sedation.</p> Methods <p>We used orexin neuron-deficient transgenic rats (orexin/ataxin-3) and wild-type controls. Noradrenaline and orexin levels were measured in the pons, hypothalamus, and cerebral cortex. Ketamine-induced loss-of-righting reflex (LORR) was assessed under modulation of noradrenergic or orexinergic activity.</p> Results <p>Wild-type rats had higher noradrenaline and orexin levels than transgenic rats across all regions except hypothalamic noradrenaline. Noradrenaline and orexin were correlated in the pons and cortex. Transgenic rats had a shorter LORR duration than wild-type rats (36.3 ± 10.4 vs. 46.7 ± 5.2&#xa0;min, P = 0.002). Noradrenergic activation via intraperitoneal yohimbine prolonged LORR in both genotypes (wild-type: 38.8 ± 4.9 vs. 71.9 ± 15.3&#xa0;min at 3.3&#xa0;mg/kg, P = 0.002; transgenic: 28.1 ± 3.9 vs. 71.9 ± 24.8&#xa0;min, P &lt; 0.001). Noradrenergic deactivation by DSP4 reduced LORR duration (wild-type: 43.3 ± 2.18 vs. 36.4 ± 6.0&#xa0;min, P = 0.005). Intracerebroventricular orexin (1.0&#xa0;nmol) shortened LORR (44.0 ± 16.7 vs. 30.1 ± 15.5&#xa0;min, P = 0.001), but co-administration of selective orexin type 1 receptor antagonist YNT-1310 (100&#xa0;nmol) counteracted this effect. Notably, orexin or DSP4 reduced LORR duration in wild-type rats but prolonged it in transgenic rats (e.g., wild-type: 40.8 ± 6.2 vs. 32.5 ± 5.3&#xa0;min with orexin, P = 0.0001; transgenic 28.6 ± 6.2 vs. 42.1 ± 5.6&#xa0;min, P = 0.0026).</p> Conclusion <p>Orexin-preserved noradrenergic activity supports the typical ketamine-induced sedation profile, highlighting their interactive role in modulating anesthetic depth.</p>

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Roles of orexinergic and noradrenergic neuronal activity in ketamine-induced sedation: a study using an orexin-ataxin-3 transgenic rat model

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  • 发表日期：

    2025年6月9日

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  • Mitsuru Tonosaki,
  • Tetsuya Kushikata,
  • Yoshikazu Nikaido,
  • Daiki Takekawa,
  • Hirotaka Kinoshita,
  • Jyunichi Saito,
  • Kazuyoshi Hirota

摘要

Purpose

To investigate the role of brain noradrenergic and orexinergic activity in ketamine-induced sedation.

Methods

We used orexin neuron-deficient transgenic rats (orexin/ataxin-3) and wild-type controls. Noradrenaline and orexin levels were measured in the pons, hypothalamus, and cerebral cortex. Ketamine-induced loss-of-righting reflex (LORR) was assessed under modulation of noradrenergic or orexinergic activity.

Results

Wild-type rats had higher noradrenaline and orexin levels than transgenic rats across all regions except hypothalamic noradrenaline. Noradrenaline and orexin were correlated in the pons and cortex. Transgenic rats had a shorter LORR duration than wild-type rats (36.3 ± 10.4 vs. 46.7 ± 5.2 min, P = 0.002). Noradrenergic activation via intraperitoneal yohimbine prolonged LORR in both genotypes (wild-type: 38.8 ± 4.9 vs. 71.9 ± 15.3 min at 3.3 mg/kg, P = 0.002; transgenic: 28.1 ± 3.9 vs. 71.9 ± 24.8 min, P < 0.001). Noradrenergic deactivation by DSP4 reduced LORR duration (wild-type: 43.3 ± 2.18 vs. 36.4 ± 6.0 min, P = 0.005). Intracerebroventricular orexin (1.0 nmol) shortened LORR (44.0 ± 16.7 vs. 30.1 ± 15.5 min, P = 0.001), but co-administration of selective orexin type 1 receptor antagonist YNT-1310 (100 nmol) counteracted this effect. Notably, orexin or DSP4 reduced LORR duration in wild-type rats but prolonged it in transgenic rats (e.g., wild-type: 40.8 ± 6.2 vs. 32.5 ± 5.3 min with orexin, P = 0.0001; transgenic 28.6 ± 6.2 vs. 42.1 ± 5.6 min, P = 0.0026).

Conclusion

Orexin-preserved noradrenergic activity supports the typical ketamine-induced sedation profile, highlighting their interactive role in modulating anesthetic depth.