HCN channels in the lateral habenula regulate pain and comorbid depressive-like behaviors in mice
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Updated: Jun 22, 2025
The Sciatic Nerve Cuffing Model of Neuropathic Pain in Mice
Published on: July 16, 2014
Xue-Zhong Cao1,2,3, Meng-Ye Zhu1,2,3, Gang Xu1,2,3
1Department of Pain Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
Insights
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the lateral habenula (LHb) contribute to anxiodepressive-like symptoms in chronic pain. Targeting HCN2 channels in the LHb alleviates pain and depressive behaviors.
Area of Science:
- Neuroscience
- Pain Research
- Behavioral Science
Background:
- Comorbid anxiodepressive-like symptoms (CADS) are linked to lateral habenula (LHb) overactivation in chronic pain.
- Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability but their role in LHb during CADS is unknown.
Purpose of the Study:
- To investigate the role of HCN channels in the LHb on CADS during chronic pain.
- To elucidate the specific HCN isoforms involved in LHb dysfunction.
Main Methods:
- Chronic neuropathic pain induced via spared nerve injury (SNI) in mice.
- Behavioral tests (sucrose preference, forced swimming, open-field, elevated plus maze) assessed anxiodepressive-like behaviors.
- Electrophysiology, immunohistochemistry, Western blotting, pharmacology, and virus knockdown explored underlying mechanisms.
Main Results:
- SNI induced anxiodepressive-like behaviors, increased LHb neuronal excitability, and enhanced HCN channel function, particularly HCN2 isoforms.
- Pharmacological inhibition or HCN2 knockdown reduced LHb excitability.
- Amelioration of both pain and depressive-like behaviors was observed after targeting HCN2.
Conclusions:
- LHb neurons exhibit hyperactivity in chronic pain with CADS.
- Enhanced HCN channel function and HCN2 up-regulation contribute to this hyperactivity.
- Targeting HCN2 channels in the LHb offers a potential therapeutic strategy for chronic pain-related mood disorders.
Aims:
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.
Conclusion:
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.
