HCN channel in the lateral habenula alleviates pain and depression comorbidity in mice

Background & Aims

Comorbid anxiodepressive-like symptoms (CADS) in chronic pain are closely related to the overactivation of the lateral habenula (LHb), The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel has been implicated playing a key role in regulating neuronal excitability and further contributing to pain maintenance and major depression. However, the role of the HCN channel in the LHb under CADS in chronic pain has not been characterized. In this study, various methods were used to illustrate the relation between increased LHb neuronal excitability and enhanced HCN channel under CADS in chronic pain.

Methods

Male wild type C57BL/6J mice (8-12 weeks of age, 20-30g) were used in all experiments. Using spared nerve injury (SNI) to establish chronic neuropathic pain and employed sucrose preference test, forced swimming test and tailed suspension test to evaluate depressive behaviors in mice, open-field test and elevated plus maze test were used to evaluate anxiety-like behaviors in mice. Immunohistochemistry and western blot were used to explore expression of the HCN channel and electrophysiology recordings were employed to detect activity of the LHb neurons. Cannula infusion experiment was used to complete microinjection of ZD7288 (an inhibitor of the HCN channel) into the LHb.

Results

We observed obvious anxiodepressive-like behaviors in SNI induced chronic neuropathic pain (NP) mice at 6 weeks after the surgery. The mice comorbid anxiodepressive-like symptoms (CADS) in NP showed increased neuronal excitability, along with enhanced function of the HCN channel and increased expression of the HCN2 isoform in the LHb. Furthermore, in vitro perfusion of ZD7288 (an inhibitor of the HCN channel) to inhibit the HCN channel significantly reduced the excitability of LHb neurons and in vivo microinjection of ZD7288 into the LHb obviously ameliorated both pain and depressive behaviors in these CADS mice. In conclusion, our results identified elevated LHb neuronal excitability, which possibly resulted from enhanced function of the HCN channel and up-regulation of the HCN2 isoform, played a key role in chronic neuropathic pain and depression comorbidity.

Conclusions

Our findings highlight the increased LHb neuronal excitability under CADS in chronic pain condition, potentially resulted from enhanced function of the HCN channel and increased expression of the HCN2 isoform. By suppressing the HCN channel activity in the LHb via local administration of ZD7288, we observed significant analgesic and antidepressant effects. These findings expand our comprehension of the cellular mechanisms underlying CADS in chronic pain and provided new insights for developing optimal treatments for patients who suffered from this comorbidity.

References

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