Ge Wen-Qiang, Zhan-Mu Ou-Yang, Chen Chao, Zhang Hong, Wang Xiao-Yu, Liu Xin, Li Li, Lan Yu-Ye, Li Chen-Nan, Sun Jia-Can, Shi Run-Lin, Dou Zi-Yue, Pan Hui-Lin, Li Hong-Ping, Jing Xiang-Hong, Li Man
Department of Neurobiology, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences (CACMS), Beijing, China.
Front Pharmacol. 2022 Sep 5;13:931600. doi: 10.3389/fphar.2022.931600. eCollection 2022.
Chronic itch severely reduces the quality of life of patients. Electroacupuncture (EA) is widely used to treat chronic itch. However, the underlying mechanism of this therapeutic action of EA is largely unknown. Cannabinoid CB1 receptors in the ventrolateral periaqueductal gray (vlPAG) mediate the analgesic effect of EA. Using a dry skin-induced itch model in mice, we determined whether EA treatment reduces chronic itch via CB1 receptors in the vlPAG. We showed that the optimal inhibitory effect of EA on chronic itch was achieved at the high frequency and high intensity (100 Hz and 3 mA) at "Quchi" (LI11) and "Hegu" (LI14) acupoints, which are located in the same spinal dermatome as the cervical skin lesions. EA reversed the increased expression of CB1 receptors in the vlPAG and decreased the concentration of 5-hydroxytryptamine (5-HT) in the medulla oblongata and the expression of gastrin-releasing peptide receptors (GRPR) in the cervical spinal cord. Furthermore, knockout of CB1 receptors on GABAergic neurons in the vlPAG attenuated scratching behavior and the 5-HT concentration in the medulla oblongata. In contrast, knockout of CB1 receptors on glutamatergic neurons in the vlPAG blocked the antipruritic effects of EA and the inhibitory effect of EA on the 5-HT concentration in the medulla oblongata. Our findings suggest that EA treatment reduces chronic itch by activation of CB1 receptors on glutamatergic neurons and inhibition of CB1 receptors on GABAergic neurons in the vlPAG, thereby inhibiting the 5-HT release from the medulla oblongata to GRPR-expressing neurons in the spinal cord. Our findings suggest that EA attenuates chronic itch activating CB1 receptors expressed on glutamatergic neurons and downregulating CB1 receptors on GABAergic neurons in the vlPAG, leading to the reduction in 5-HT release in the rostroventral medulla and GRPR signaling in the spinal cord. Our study not only advances our understanding of the mechanisms of the therapeutic effect of EA on chronic itch but also guides the selection of optimal parameters and acupoints of EA for treating chronic itch.
慢性瘙痒严重降低患者的生活质量。电针（EA）被广泛用于治疗慢性瘙痒。然而，EA这种治疗作用的潜在机制在很大程度上尚不清楚。腹外侧导水管周围灰质（vlPAG）中的大麻素CB1受体介导EA的镇痛作用。利用小鼠干性皮肤诱导的瘙痒模型，我们确定EA治疗是否通过vlPAG中的CB1受体减轻慢性瘙痒。我们发现，在位于与颈部皮肤损伤相同脊髓节段皮节的“曲池”（LI11）和“合谷”（LI14）穴位，以高频高强度（100Hz和3mA）进行EA治疗，对慢性瘙痒具有最佳抑制作用。EA可逆转vlPAG中CB1受体表达的增加，并降低延髓中5-羟色胺（5-HT）的浓度以及颈脊髓中胃泌素释放肽受体（GRPR）的表达。此外，vlPAG中GABA能神经元上CB1受体的敲除减弱了搔抓行为以及延髓中5-HT的浓度。相反，vlPAG中谷氨酸能神经元上CB1受体的敲除阻断了EA的止痒作用以及EA对延髓中5-HT浓度的抑制作用。我们的研究结果表明，EA治疗通过激活vlPAG中谷氨酸能神经元上的CB1受体并抑制GABA能神经元上的CB1受体来减轻慢性瘙痒，从而抑制5-HT从延髓释放到脊髓中表达GRPR的神经元。我们的研究结果表明，EA通过激活vlPAG中谷氨酸能神经元上表达的CB1受体并下调GABA能神经元上的CB1受体来减轻慢性瘙痒，从而导致延髓腹侧前部5-HT释放减少以及脊髓中GRPR信号传导减少。我们的研究不仅增进了我们对EA治疗慢性瘙痒作用机制的理解，还为治疗慢性瘙痒的EA最佳参数和穴位选择提供了指导。
