Geraniol enhances inhibitory inputs to the paraventricular thalamic nucleus and induces sedation in mice

Ling Xu; Ming-Zhe Liu; Ya-Yue Yang; Yan Wang; Xiao-Xiao Hua; Li-Xia Du; Jian-Yu Zhu; Yang Shen; Yan-Qing Wang; Ling Zhang; Wen-Li Mi; Di Mu

doi:10.1016/j.phymed.2022.153965

Geraniol enhances inhibitory inputs to the paraventricular thalamic nucleus and induces sedation in mice

Phytomedicine. 2022 Apr:98:153965. doi: 10.1016/j.phymed.2022.153965. Epub 2022 Jan 29.

Authors

Ling Xu¹, Ming-Zhe Liu², Ya-Yue Yang³, Yan Wang¹, Xiao-Xiao Hua⁴, Li-Xia Du³, Jian-Yu Zhu³, Yang Shen¹, Yan-Qing Wang⁵, Ling Zhang⁴, Wen-Li Mi⁶, Di Mu⁷

Affiliations

¹ Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
² Department of Respiratory, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
³ Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, Institutes of Brain Science, Medical College, Fudan University, Shanghai 200032, China.
⁴ The First Rehabilitation Hospital of Shanghai, Tongji University School of Medicine, Shanghai 200090, China.
⁵ Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, Institutes of Brain Science, Medical College, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory for Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai 200433, China.
⁶ Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, Institutes of Brain Science, Medical College, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory for Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai 200433, China. Electronic address: wenlimi@fudan.edu.cn.
⁷ SUSTech Center for Pain Medicine, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China; Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China. Electronic address: dimu08207@ustc.edu.

PMID: 35144136
DOI: 10.1016/j.phymed.2022.153965

Abstract

Background: Plant extracts with sedative effects have a long history of clinical use for treating insomnia and epilepsy. Geraniol (GE), a plant-derived acyclic monoterpene, reduces locomotion and prolongs barbiturate-induced anesthesia in rats. However, the mechanisms of GE in sedation remain elusive.

Purpose: This study aimed to investigate the mechanisms of GE in sedation in mice.

Methods: GE was administered systemically by nebulization and intraperitoneal injection. Open field tests, acute seizure tests, and electroencephalogram (EEG) recordings were performed to examine the sedative effects of GE in mice. The time of loss of the righting reflex and return of the righting reflex were recorded in anesthesia experiments to examine the effect of GE on anesthesia. In vitro c-Fos staining and in vivo fiber photometry recordings were performed to detect the activity change of the paraventricular thalamic nucleus (PVT). Microinjection of GE into PVT and related behavioral tests were performed to confirm that PVT was a critical target for GE. Whole-cell recordings were performed to dissect the effects of GE on PVT neurons via GABA_A receptors. Molecular docking was performed to examine the interaction between GE and GABA_A receptor subunits.

Results: We found that GE reduced locomotion, relieved acute seizures, altered the EEG, and facilitated general anesthesia in mice. Next, we found that GE decreased c-Fos expression and suppressed the calcium activity in PVT. Microinjection of GE into PVT reduced locomotion and facilitated anesthesia. Furthermore, electrophysiology results showed that GE induced dramatic membrane hyperpolarization and suppressed the activity of PVT neurons, mainly by prolonging spontaneous inhibitory postsynaptic currents and inducing tonic inhibitory currents. Molecular docking results indicated that the β3 subunit might be a potential target for GE.

Conclusion: By combined using behavioral tests, immunohistochemistry, calcium recording, and electrophysiology, we systematically revealed that GE inhibits PVT and induces sedation in mice. Essential oils have long been considered part of traditional medicine, and they are playing a critical role in aromatherapy. Since GE has a comparatively ideal safety property and multiple delivery methods, GE has great application potential in aromatherapy. Our study also provides a potential candidate for further development of sedatives and anaesthetics.

Keywords: GABA(A) receptors; Geraniol; Paraventricular thalamic nucleus; Sedation; Tonic inhibition.