The Slack Channel Deletion Causes Mechanical Pain Hypersensitivity in Mice

Ye Liu; Fang-Fang Zhang; Ying Song; Ran Wang; Qi Zhang; Zhong-Shan Shen; Fei-Fei Zhang; Dan-Ya Zhong; Xiao-Hui Wang; Qing Guo; Qiong-Yao Tang; Zhe Zhang

doi:10.3389/fnmol.2022.811441

The Slack Channel Deletion Causes Mechanical Pain Hypersensitivity in Mice

Front Mol Neurosci. 2022 Mar 11:15:811441. doi: 10.3389/fnmol.2022.811441. eCollection 2022.

Authors

Ye Liu^{1

2

3}, Fang-Fang Zhang^{1

2

3}, Ying Song^{1

2

3}, Ran Wang^{1

2}, Qi Zhang^{1

2

3}, Zhong-Shan Shen^{1

2

3}, Fei-Fei Zhang^{1

2

3}, Dan-Ya Zhong^{1

2

3}, Xiao-Hui Wang^{1

2

3}, Qing Guo^{1

2

3}, Qiong-Yao Tang^{1

2

3}, Zhe Zhang^{1

2

3}

Affiliations

¹ Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China.
² Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
³ NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China.

Abstract

The role of the Slack (also known as Slo2.2, K_Na1.1, or KCNT1) channel in pain-sensing is still in debate on which kind of pain it regulates. In the present study, we found that the Slack^-/- mice exhibited decreased mechanical pain threshold but normal heat and cold pain sensitivity. Subsequently, X-gal staining, in situ hybridization, and immunofluorescence staining revealed high expression of the Slack channel in Isolectin B4 positive (IB4⁺) neurons in the dorsal root ganglion (DRG) and somatostatin-positive (SOM⁺) neurons in the spinal cord. Patch-clamp recordings indicated the firing frequency was increased in both small neurons in DRG and spinal SOM⁺ neurons in the Slack^-/- mice whereas no obvious slow afterhyperpolarization was observed in both WT mice and Slack^-/- mice. Furthermore, we found Kcnt1 gene expression in spinal SOM⁺ neurons in Slack^-/- mice partially relieved the mechanical pain hypersensitivity of Slack^-/- mice and decreased AP firing rates of the spinal SOM⁺ neurons. Finally, deletion of the Slack channel in spinal SOM⁺ neurons is sufficient to result in mechanical pain hypersensitivity in mice. In summary, our results suggest the important role of the Slack channel in the regulation of mechanical pain-sensing both in small neurons in DRG and SOM⁺ neurons in the spinal dorsal horn.

Keywords: DRG neurons; SOM+ neurons; Slack channel; mechanical pain; potassium channel.