Upregulation of ubiquitin conjugating enzyme E2B (Ube2b) ameliorates neuropathic pain by regulating Kcna2 (potassium voltage-gated channel subfamily A member 2) in primary afferent neurons

ABSTRACT

Neuropathic pain is a kind of pain caused by damage to somatosensory nervous system. Currently, neuropathic pain is still a medical problem for clinicians. Ubiquitin conjugating enzyme E2B (Ube2b) is validated to be implicated with nerve function, but whether Ube2b can play a role in neuropathic pain is still elusive. In this work, we constructed chronic constriction injury (CCI) rat model by ligating the left sciatic nerve, Ube2b protein expression was confirmed to be decreased in spinal cord tissues of CCI rats via Western blot analysis and immunofluorescence (IF) staining. Moreover, Ube2b elevation alleviated the thermal hyperalgesia and mechanical hyperalgesia in CCI rats according to paw withdrawal thermal latency (PWTL) and paw withdrawal mechanic threshold (PWMT). In addition, Hematoxylin-eosin staining revealed that Ube2b elevation suppressed chronic sciatic nerve injury. All these data suggested that Ube2b could ameliorate neuropathic pain in CCI rats. Mechanically, Ube2b upregulation elevated the protein level of Kcna2 (potassium voltage-gated channel subfamily A member 2) and decreased the protein level of DNMT3a (DNA methyltransferase 3 alpha). Ube2b elevation could increase Kcna2 expression via suppressing DNMT3a. Rescue assays unveiled that Ube2b overexpression modulated-mechanical hyperalgesia and thermal hyperalgesia were reversed by Kcna2 depletion, indicating that Ube2b alleviated neuropathic pain via mediating Kcna2 via the regulation of DNMT3a. In summary, we found that Ube2b elevation ameliorated neuropathic pain through regulating Kcna2, which might offer a novel biomarker for the therapies of neuropathic pain.

KEYWORDS:

• Ube2b
• DNMT3a
• Kcna2
• neuropathic pain

Disclosure statement

The authors state that there are no conflicts of interest to disclose.

Contribution of authors

Yuanzhi Peng and Qingqing Zhang designed the study, supervised the data collection, Hao Cheng analyzed the data, interpreted the data, Guizhen Yan and Chunli Xing prepare the manuscript for publication and reviewed the draft of the manuscript. All authors have read and approved the manuscript.

Ethics approval

Ethical approval was obtained from the Ethics Committee of Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University (Approval No. XHEC-D-2018-082).

Highlight

1. Ube2b expression was decreased in CCI rats.

2. Ube2b elevation alleviated the mechanical hyperalgesia and thermal hyperalgesia in rats.

3. Ube2b elevation suppressed chronic sciatic nerve injury.

4. Ube2b regulated the expression of DNMT3a and Kcna2.

5. Ube2b promoted the level of Kcna2 via regulating DNMT3a.

6. Ube2b modulated neuropathic pain via mediating Kcna2.

Additional information

Funding

The authors have no funding to report.