目的:慢性疼痛伴发的焦虑抑郁样症状(CADS)与侧突肌过度激活(LHb)密切相关。超极化激活的环核苷酸门控(HCN)通道在调节神经元兴奋性中起关键作用。然而,在CADS期间,HCN通道在LHb中的作用尚未明确.本研究旨在探讨LHb中HCN通道对慢性疼痛CADS的影响。
方法:保留神经损伤(SNI)诱发慢性神经性疼痛后,小鼠接受了蔗糖偏好测试,强迫游泳测试,尾部悬挂试验,露天试验,和高架迷宫测试来评估他们的焦虑抑郁样行为。电生理记录,免疫组织化学,西方印迹,药理实验,和病毒敲除策略被用来研究潜在的机制。
结果:SNI手术后6w观察到明显的焦虑抑郁样行为,伴随着神经元兴奋性的增加,增强HCN通道功能,和LHb中HCN2亚型的表达增加。HCN2通道的药理学抑制或病毒敲除均显着降低了LHb神经元的兴奋性,并改善了疼痛和抑郁样行为。
结论:我们的结果表明,在慢性疼痛的CADS下,LHb神经元是过度活跃的,这种过度激活可能是由于HCN通道的功能增强和HCN2亚型的上调所致。
OBJECTIVE: Comorbid anxiodepressive-like symptoms (CADS) in chronic pain are closely related to the overactivation of the lateral habenula (LHb). Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been implicated to play a key role in regulating neuronal excitability. However, the role of HCN channels in the LHb during CADS has not yet been characterized. This study aimed to investigate the effect of HCN channels in the LHb on CADS during chronic pain.
METHODS: After chronic neuropathic pain induction by spared nerve injury (SNI), mice underwent a sucrose preference test, forced swimming test, tail suspension test, open-field test, and elevated plus maze test to evaluate their anxiodepressive-like behaviors. Electrophysiological recordings, immunohistochemistry, Western blotting, pharmacological experiments, and virus knockdown strategies were used to investigate the underlying mechanisms.
RESULTS: Evident anxiodepressive-like behaviors were observed 6w after the SNI surgery, accompanied by increased neuronal excitability, enhanced HCN channel function, and increased expression of HCN2 isoforms in the LHb. Either pharmacological inhibition or virus knockdown of HCN2 channels significantly reduced LHb neuronal excitability and ameliorated both pain and depressive-like behaviors.
CONCLUSIONS: Our results indicated that the LHb neurons were hyperactive under CADS in chronic pain, and this hyperactivation possibly resulted from the enhanced function of HCN channels and up-regulation of HCN2 isoforms.