Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-β superfamily. It is widely distributed in the central and peripheral nervous systems. Whether and how GDF-15 modulates nociceptive signaling remains unclear. Behaviorally, we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naïve and arthritic rats. Electrophysiologically, we demonstrated that GDF-15 decreased the excitability of small-diameter dorsal root ganglia (DRG) neurons. Furthermore, GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents, and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction. GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels, suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel. Immunohistochemistry results showed that activin receptor-like kinase-2 (ALK2) was widely expressed in DRG medium- and small-diameter neurons, and some of them were Nav1.8-positive. Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors. Inhibition of PKA and ERK, but not PKC, blocked the inhibitory effect of GDF-15 on Nav1.8 currents. These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK, which mediate the peripheral analgesia of GDF-15.

生长分化因子 15 (GDF-15) 是转化生长因子-β 超家族的成员。它广泛分布于中枢和外周神经系统。GDF-15 是否以及如何调节伤害性信号传导尚不清楚。在行为上，我们发现外周 GDF-15 显着提高了幼稚和关节炎大鼠对机械和热刺激的伤害性反应阈值。在电生理学上，我们证明 GDF-15 降低了小直径背根神经节 (DRG) 神经元的兴奋性。此外，GDF-15 浓度依赖性地抑制河豚毒素抗性钠通道 Nav1.8 电流，并使 Nav1.8 的稳态失活曲线向超极化方向移动。GDF-15 还降低了窗口电流并减慢了 Nav1.8 通道的恢复速度，表明 GDF-15 加速了失活并减慢了通道的恢复。免疫组化结果显示激活素受体样激酶2（ALK2）在DRG中小直径神经元中广泛表达，部分神经元Nav1.8阳性。ALK2 的阻断阻止了 GDF-15 诱导的 Nav1.8 电流和伤害性行为的抑制。PKA 和 ERK 的抑制，但不是 PKC，阻止了 GDF-15 对 Nav1.8 电流的抑制作用。这些结果表明 DRG 神经元中 GDF-15 和 Nav1.8 之间存在功能联系 8 电流和伤害性行为。PKA 和 ERK 的抑制，但不是 PKC，阻止了 GDF-15 对 Nav1.8 电流的抑制作用。这些结果表明 DRG 神经元中 GDF-15 和 Nav1.8 之间存在功能联系 8 电流和伤害性行为。PKA 和 ERK 的抑制，但不是 PKC，阻止了 GDF-15 对 Nav1.8 电流的抑制作用。这些结果表明 DRG 神经元中 GDF-15 和 Nav1.8 之间存在功能联系通过ALK2 受体和与 MEK/ERK 相关的 PKA，介导 GDF-15 的外周镇痛。