Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.
Nat Commun. 2013;4:1682. doi: 10.1038/ncomms2673.
Aberrant mechanosensation has an important role in different pain states. Here we show that Epac1 (cyclic AMP sensor) potentiation of Piezo2-mediated mechanotransduction contributes to mechanical allodynia. Dorsal root ganglia Epac1 mRNA levels increase during neuropathic pain, and nerve damage-induced allodynia is reduced in Epac1-/- mice. The Epac-selective cAMP analogue 8-pCPT sensitizes mechanically evoked currents in sensory neurons. Human Piezo2 produces large mechanically gated currents that are enhanced by the activation of the cAMP-sensor Epac1 or cytosolic calcium but are unaffected by protein kinase C or protein kinase A and depend on the integrity of the cytoskeleton. In vivo, 8-pCPT induces long-lasting allodynia that is prevented by the knockdown of Epac1 and attenuated by mouse Piezo2 knockdown. Piezo2 knockdown also enhanced thresholds for light touch. Finally, 8-pCPT sensitizes responses to innocuous mechanical stimuli without changing the electrical excitability of sensory fibres. These data indicate that the Epac1-Piezo2 axis has a role in the development of mechanical allodynia during neuropathic pain.
异常的机械感觉在不同的疼痛状态中起着重要作用。在这里，我们表明 Epac1（环 AMP 传感器）增强 Piezo2 介导的机械转导有助于机械性痛觉过敏。在神经病理性疼痛期间，背根神经节 Epac1 mRNA 水平增加，而 Epac1-/- 小鼠的神经损伤诱导的痛觉过敏减少。Epac 选择性 cAMP 类似物 8-pCPT 敏化感觉神经元中机械诱发的电流。人类 Piezo2 产生大的机械门控电流，该电流可通过激活 cAMP 传感器 Epac1 或细胞质钙增强，但不受蛋白激酶 C 或蛋白激酶 A 的影响，并且依赖于细胞骨架的完整性。在体内，8-pCPT 诱导持久的痛觉过敏，这种痛觉过敏可被 Epac1 的敲低预防，并且可被小鼠 Piezo2 的敲低减弱。Piezo2 的敲低也增强了对轻触的阈值。最后，8-pCPT 增强了对无害机械刺激的反应，而不改变感觉纤维的电兴奋性。这些数据表明，在神经病理性疼痛期间，Epac1-Piezo2 轴在机械性痛觉过敏的发展中起作用。
