Dataset Information

The Slack Channel Deletion Causes Mechanical Pain Hypersensitivity in Mice.

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.

SUBMITTER: Liu Y

PROVIDER: S-EPMC8963359 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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The Slack Channel Deletion Causes Mechanical Pain Hypersensitivity in Mice.

Liu Ye Y Zhang Fang-Fang FF Song Ying Y Wang Ran R Zhang Qi Q Shen Zhong-Shan ZS Zhang Fei-Fei FF Zhong Dan-Ya DY Wang Xiao-Hui XH Guo Qing Q Tang Qiong-Yao QY Zhang Zhe Z

Frontiers in molecular neuroscience 20220311

The role of the Slack (also known as Slo2.2, KNa1.1, 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 t ...[more]

PMID: 35359569

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Project description:Inflammation is known to be responsible for the sensitization of peripheral sensory neurons, leading to spontaneous pain and invalidating pain hypersensitivity. Given its role in regulating neuronal excitability, the voltage-gated Nav1.9 channel is a potential target for the treatment of pathological pain, but its implication in inflammatory pain is yet not fully described. In the present study, we examined the role of the Nav1.9 channel in acute, subacute and chronic inflammatory pain using Nav1.9-null mice and Nav1.9 knock-down rats. In mice we found that, although the Nav1.9 channel does not contribute to basal pain thresholds, it plays an important role in heat pain hypersensitivity induced by subacute paw inflammation (intraplantar carrageenan) and chronic ankle inflammation (complete Freund's adjuvant-induced monoarthritis). We showed for the first time that Nav1.9 also contributes to mechanical hypersensitivity in both models, as assessed using von Frey and dynamic weight bearing tests. Consistently, antisense-based Nav1.9 gene silencing in rats reduced carrageenan-induced heat and mechanical pain hypersensitivity. While no changes in Nav1.9 mRNA levels were detected in dorsal root ganglia (DRGs) during subacute and chronic inflammation, a significant increase in Nav1.9 immunoreactivity was observed in ipsilateral DRGs 24 hours following carrageenan injection. This was correlated with an increase in Nav1.9 immunolabeling in nerve fibers surrounding the inflamed area. No change in Nav1.9 current density could be detected in the soma of retrolabeled DRG neurons innervating inflamed tissues, suggesting that newly produced channels may be non-functional at this level and rather contribute to the observed increase in axonal transport. Our results provide evidence that Nav1.9 plays a crucial role in the generation of heat and mechanical pain hypersensitivity, both in subacute and chronic inflammatory pain models, and bring new elements for the understanding of its regulation in those models.

Dataset Information

The Slack Channel Deletion Causes Mechanical Pain Hypersensitivity in Mice.

Publications

The Slack Channel Deletion Causes Mechanical Pain Hypersensitivity in Mice.

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