Growth Differentiation Factor-15 Produces Analgesia by Inhibiting Tetrodotoxin-Resistant Nav1.8 Sodium Channel Activity in Rat Primary Sensory Neurons  

作　　者：Wei Lin Wen-Wen Zhang Ning Lyu Hong Cao Wen-Dong Xu Yu-Qiu Zhang 

机构地区：[1]Department of Translational Neuroscience,Jing’an District Centre Hospital of Shanghai,State Key Laboratory of Medical Neurobiology and Institutes of Brain Science,Fudan University,Shanghai 200032,China [2]Department of Hand Surgery,Huashan Hospital,Fudan University,Shanghai 200040,China [3]Department of Neurobiology,School of Basic Medical Sciences,Shanghai Medical College,Fudan University,Shanghai 200032,China

出　　处：《Neuroscience Bulletin》2021年第9期1289-1302,共14页神经科学通报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(82021002,31771164,and 31930042);the National Key R&D Program of China(2017YFB0403803);the Innovative Research Team of High-level Local Universities in Shanghai,Shanghai Municipal Science and Technology Major Project(2018SHZDZX01);Zhang Jiang Laboratory.

摘　　要：Growth differentiation factor 15(GDF-15)is a member of the transforming growth factor-βsuperfamily.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.

关 键 词：Growth differentiation factor-15 Tetrodotoxin-resistant sodium channel NAV1.8 Dorsal root ganglion Whole-cell recording Activin receptor-like kinase-2 PAIN 

分 类 号：R402[医药卫生—临床医学]