HCN通道在大鼠模型性三叉神经痛中的作用及其调制机制

Trigeminal neuralgia (TN) is a neurologic disorder characterized by paroxysmal and unpredictable attacks of facial pain, which severely affects patients’ quality of life. Currently, there are mainly three treatment options available for refractory TN: microvascular decompression (MVD), Gamma Knife surgery (GKS), and gasserian ganglion percutaneous techniques. However, these methods only provide temporarily relief among some patients and TN may relapse after successful surgery procedure. In other patients, these treatments are not effective at all and TN persists after surgery. Studies have suggested that Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are widely expressed in nerve system and play an important role in neuropathic pain. Our recent study show that inhibition of HCN channels in the VPL region of the thalamus by HCN channel inhibitor ZD7288 reduced the nociceptive behavior in rats with neuropathic pain or chronic arthritis in rats. Studies by others have shown that HCN is highly expressed in the gasserian ganglion in rats.Taken together, these data indicate that HCN channel may regulate the neuronal excitation in the gasserian ganglion and HCN channels may be a target for the treatment of TN. We propose to study the distribution of HCN isoforms in the gasserian ganglion and the role of each isoform in the TN model we recently established. We will also investigate the behavioral effects of HCN channel inhibitor on the TN rats. Furthermore, we will investigate the mechanism underlying the HCN channel activation in TN. The results will reveal the role of HCN channel in the development and maintenance of TN, and provide new treatment target of TN.

三叉神经痛（TN）是神经功能紊乱造成无法预知的发作性面部疼痛，严重影响患者生活质量。目前药物、微创和手术治疗效果均不理想。大量研究证实超极化环核苷酸门控阳离子通道（HCN）在神经系统广泛分布并产生超极化电流(Ih)调节神经元兴奋性且与神经病理性疼痛密切相关。 课题组在动物研究发现大鼠丘脑腹后外侧核HCN通道阻滞可以显著缓解坐骨神经痛和关节痛，在大鼠三叉神经节也有HCN表达 ，提示HCN离子通道不仅可能参与TN形成的病理生理过程，而且可以作为治疗TN的新靶点。本课题拟研究三叉神经节内HCN亚型分布及各亚型在我们前期建立的改良TN模型中的表达方式，并研究三叉神经节HCN通道阻滞对TN大鼠的行为学影响及其作用机理。所得的结果不仅可以揭示HCN在TN发生和发展过程中的作用、明确该通道阻滞对TN的调控效应和电生理机制，同时为TN的新型治疗手段提供理论依据。

三叉神经痛（TN）是神经功能紊乱造成无法预知的发作性面部疼痛，严重影响患者生活质量。目前药物、微创和手术治疗效果均不理想。大量研究证实超极化环核苷酸门控阳离子通道（HCN）在神经系统广泛分布并产生超极化电流(Ih)调节神经元兴奋性且与神经病理性疼痛密切相关。课题组在动物研究发现大鼠丘脑腹后外侧核HCN通道阻滞可以显著缓解坐骨神经痛和关节痛，在大鼠三叉神经节也有HCN表达 ，提示HCN离子通道不仅可能参与TN形成的病理生理过程，而且可以作为治疗TN的新靶点。课题组首先顺利建立了创伤更小、操作更简单且术后动物行为学更稳定的大鼠三叉神经痛模型，为疼痛机制的研究奠定了坚实的基础。接着，课题组揭示了HCN通道在三叉神经节初级感觉神经元中促进三叉神经痛疼痛慢性化的机制；针对在外周初级感觉神经元观察到的研究结果，对中枢神经系统三叉神经痛疼痛传导通路驿站-丘脑进行了延展性研究，结果表明丘脑腹后内侧核VPL中HCN-1和HCN-2离子通道同样促进了三叉神经痛的形成与发展，同时通过选择性离子通道阻滞不仅改善了大鼠三叉神经痛，而且逆转了三叉神经痛继发的认知功能损伤；最后通过AAV与慢病毒工具分别在初级感觉传入中枢和丘脑水平初步验证了基因沉默治疗大鼠三叉神经痛的可行性和有效性。本研究将为三叉神经痛的临床转化研究提供了理论参考依据。