Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
National Health Commission Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Science (CAMS) & Peking Union Medical College (PUMC), Beijing 100101, China.
Int J Mol Sci. 2023 Sep 7;24(18):13823. doi: 10.3390/ijms241813823.
Chronic pain is a significant health problem worldwide. Recent evidence has suggested that the ventral hippocampus is dysfunctional in humans and rodents, with decreased neuronal excitability and connectivity with other brain regions, parallel pain chronicity, and persistent nociceptive hypersensitivity. But the molecular mechanisms underlying hippocampal modulation of pain remain poorly elucidated. In this study, we used ex vivo whole-cell patch-clamp recording, immunofluorescence staining, and behavioral tests to examine whether hyperpolarization-activated cyclic nucleotide-gated channels 2 (HCN2) in the ventral hippocampal CA1 (vCA1) were involved in regulating nociceptive perception and CFA-induced inflammatory pain in mice. Reduced sag potential and firing rate of action potentials were observed in vCA1 pyramidal neurons from CFA-injected mice. Moreover, the expression of HCN2, but not HCN1, in vCA1 decreased in mice injected with CFA. HCN2 knockdown in vCA1 pyramidal neurons induced thermal hypersensitivity, whereas overexpression of HCN2 alleviated thermal hyperalgesia induced by intraplantar injection of CFA in mice. Our findings suggest that HCN2 in the vCA1 plays an active role in pain modulation and could be a promising target for the treatment of chronic pain.
慢性疼痛是一个全球性的重大健康问题。最近的证据表明，腹侧海马体在人类和啮齿动物中功能失调，表现为神经元兴奋性降低，与其他脑区的连接减少，与疼痛慢性化和持续性伤害感受过敏平行。但是，海马体调节疼痛的分子机制仍未得到充分阐明。在这项研究中，我们使用了离体全细胞膜片钳记录、免疫荧光染色和行为学测试，以研究腹侧海马体 CA1（vCA1）中的超极化激活环核苷酸门控通道 2（HCN2）是否参与调节小鼠的伤害感受和 CFA 诱导的炎性疼痛。在 CFA 注射的小鼠中，vCA1 锥体神经元的去极化电位和动作电位发放率降低。此外，在注射 CFA 的小鼠中，vCA1 中的 HCN2 表达减少，而 HCN1 的表达不变。vCA1 锥体神经元中的 HCN2 敲低可诱导热敏感性增加，而 vCA1 中的 HCN2 过表达可减轻 CFA 足底注射诱导的热痛觉过敏。我们的研究结果表明，vCA1 中的 HCN2 在疼痛调节中起着积极的作用，可能是治疗慢性疼痛的有前途的靶点。
