Mechanically activated, slowly adapting currents in sensory neurons have been linked to noxious mechanosensation. The conotoxin NMB-1 (noxious mechanosensation blocker-1) blocks such currents and inhibits mechanical pain. Using a biotinylated form of NMB-1 in mass spectrometry analysis, we identified 67 binding proteins in sensory neurons and a sensory neuron–derived cell line, of which the top candidate was annexin A6, a membrane-associated calcium-binding protein. Annexin A6–deficient mice showed increased sensitivity to mechanical stimuli. Sensory neurons from these mice showed increased activity of the cation channel Piezo2, which mediates a rapidly adapting mechano-gated current linked to proprioception and touch, and a decrease in mechanically activated, slowly adapting currents. Conversely, overexpression of annexin A6 in sensory neurons inhibited rapidly adapting currents that were partially mediated by Piezo2. Furthermore, overexpression of annexin A6 in sensory neurons attenuated mechanical pain in a mouse model of osteoarthritis, a disease in which mechanically evoked pain is particularly problematic. These data suggest that annexin A6 can be exploited to inhibit chronic mechanical pain.

感觉神经元中机械激活、缓慢适应的电流与有害的机械感觉有关。芋螺毒素 NMB-1（有害机械感觉阻滞剂 1）可阻断此类电流并抑制机械性疼痛。在质谱分析中使用生物素化形式的 NMB-1，我们在感觉神经元和感觉神经元衍生细胞系中鉴定了 67 种结合蛋白，其中最佳候选者是膜联蛋白 A6，一种膜相关的钙结合蛋白。膜联蛋白 A6 缺陷小鼠对机械刺激的敏感性增加。这些小鼠的感觉神经元表现出阳离子通道 Piezo2 的活性增加，该通道介导与本体感觉和触觉相关的快速适应的机械门控电流，以及机械激活的缓慢适应电流的减少。反过来，感觉神经元中膜联蛋白 A6 的过表达抑制了部分由 Piezo2 介导的快速适应电流。此外，感觉神经元中膜联蛋白 A6 的过度表达减轻了骨关节炎小鼠模型中的机械疼痛，这种疾病的机械诱发疼痛尤其成问题。这些数据表明可以利用膜联蛋白 A6 来抑制慢性机械性疼痛。