Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States.
Pain. 2023 Aug 1;164(8):1874-1886. doi: 10.1097/j.pain.0000000000002889. Epub 2023 Mar 10.
Debilitating pain affects the lives of patients with sickle cell disease (SCD). Current pain treatment for patients with SCD fail to completely resolve acute or chronic SCD pain. Previous research indicates that the cation channel transient receptor potential vanilloid type 4 (TRPV4) mediates peripheral hypersensitivity in various inflammatory and neuropathic pain conditions that may share similar pathophysiology with SCD, but this channel's role in chronic SCD pain remains unknown. Thus, the current experiments examined whether TRPV4 regulates hyperalgesia in transgenic mouse models of SCD. Acute blockade of TRPV4 alleviated evoked behavioral hypersensitivity to punctate, but not dynamic, mechanical stimuli in mice with SCD. TRPV4 blockade also reduced the mechanical sensitivity of small, but not large, dorsal root ganglia neurons from mice with SCD. Furthermore, keratinocytes from mice with SCD showed sensitized TRPV4-dependent calcium responses. These results shed new light on the role of TRPV4 in SCD chronic pain and are the first to suggest a role for epidermal keratinocytes in the heightened sensitivity observed in SCD.
致残性疼痛影响镰状细胞病 (SCD) 患者的生活。目前 SCD 患者的疼痛治疗未能完全解决急性或慢性 SCD 疼痛。先前的研究表明，阳离子通道瞬时受体电位香草素 4 (TRPV4) 介导各种炎症和神经病理性疼痛情况下的外周超敏反应，这些疼痛可能与 SCD 具有相似的病理生理学，但该通道在慢性 SCD 疼痛中的作用尚不清楚。因此，目前的实验研究了 TRPV4 是否调节 SCD 转基因小鼠模型中的痛觉过敏。TRPV4 的急性阻断减轻了 SCD 小鼠对点状而非动态机械刺激的诱发行为性超敏反应。TRPV4 阻断还降低了 SCD 小鼠小而不是大背根神经节神经元的机械敏感性。此外，SCD 小鼠的角质形成细胞表现出 TRPV4 依赖性钙反应的致敏。这些结果为 TRPV4 在 SCD 慢性疼痛中的作用提供了新的认识，并且首次表明表皮角质形成细胞在 SCD 中观察到的敏感性增加中起作用。
