外侧僵核HCN通道在慢性疼痛伴发抑郁中的作用及机制研究

The development of chronic pain is closely associated with negative emotions like depression. Combination of these two disorders may exacerbate patients suffering and cause obstacles for their clinical treatment. The lateral habenula (LHb) is a major brain region involved in the pathogenesis of depression, and it has been implicated that a depression-state depends critically on the excitation of LHb neurons. Meanwhile, as a relay site in the transmission of nociceptive information, LHb also plays a crucial role in pain processing. As recently shown, one characteristic of enhanced LHb neuron excitability is increased burst activity. Our previous studies found that burst firing could be regulated by hyperpolarization-activated nucleotide-gated (HCN) channels which are highly related with both chronic pain and depression. Genetic mutation or pharmacological blockade of HCN channels lead to a delay in firing the first sodium spike, together with a reduction in the total number of spikes in bursting. HCN channels are expressed in the LHb nuclei; however, their expression changes within LHb in chronic pain-associated depression have not been addressed. Therefore, we hypothesize that chronification of pain may result in HCN channelopathy which would further induce strong bursts in LHb, alter neuronal excitability and cause comorbid depression. Using behavioral, electrophysiological and immunohistochemistrical methods, we will elucidate the role of HCN channels in LHb in chronic pain-associated depression, and thus provide a new framework for developing therapeutic strategies.

慢性疼痛患者常伴随不同程度的抑郁等负性情绪，两种疾病相互影响，使临床治疗更为艰难。外侧僵核（LHb）是参与抑郁形成的关键脑区，其内神经元过度兴奋是核心机制。作为伤害性信息传递整合的中继站，LHb在慢性疼痛发生发展中亦起重要作用。研究表明，burst放电增加是LHb神经元兴奋性上调的特征表现。我们前期研究发现，与慢性疼痛和抑郁均密切相关的超极化激活阳离子（HCN）通道介导的内向电流是影响burst放电的重要因素：敲除或阻断HCN通道可延长burst放电潜伏期、减少动作电位发放。LHb内HCN通道高度表达，但慢性疼痛伴发抑郁时，该通道表达如何变化尚不清楚。因此我们推测，慢性疼痛时，LHb区HCN通道表达异常致神经元burst放电增加、兴奋性上调可能是其伴发抑郁的关键机制。本项目拟结合行为学、电生理学及免疫组织化学等技术，揭示LHb区HCN通道在慢性疼痛伴发抑郁中的作用，为其临床防治提供新思路。

慢性疼痛患者常伴随抑郁焦虑等负性情绪，抑郁情绪的滋生又可加剧患者的疼痛感受，而当前的镇痛策略或抗抑郁策略对此类患者疗效不佳，究其原因可能是当前慢性疼痛抑郁共病的中枢神经机制尚不清楚。外侧缰核（Lateral habenula，LHb）已被证实是既参与负性情绪调控、又在疼痛信息编码中发挥关键作用的重要脑区，该核团过度兴奋早已被证实为抑郁症发病的核心机制之一；亦有研究证实慢性疼痛状态下，LHb可被过度激活，但在慢性疼痛抑郁共病状态下，LHb内神经元兴奋性如何变化尚未明确。超极化激活环核苷酸阳离子（Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels，HCN）通道已被证实可通过影响外周和中枢神经系统多个脑区神经元电活动进一步调控疼痛及情绪障碍，且HCN通道4种亚型在LHb内高表达，但在慢性疼痛抑郁共病形成过程中LHb内HCN通道扮演何种角色目前尚不可知。针对这些未知，本项目采用保留坐骨神经损伤（Spared nerve injury，SNI）方法建立慢性疼痛抑郁共病小鼠模型，结合行为学、电生理学、免疫组织化学、western blot、脑立体及药理学等实验技术阐明了：1）慢性疼痛抑郁共病状态下，LHb内HCN通道功能增强伴HCN2表达增加，进一步导致LHb神经元兴奋性增加；2）慢性疼痛抑郁共病状态下，LHb区兴奋性突触传递增强，抑制性突触传递减弱；3）药理学抑制LHb区HCN通道可显著改善慢性疼痛抑郁共病小鼠痛行为及抑郁样行为。以上研究结果以HCN通道为切入点揭示慢性疼痛抑郁共病的神经机制，为慢性疼痛抑郁共病的临床防治提供新的理论基础和治疗靶点。