Growth Differentiation Factor-15 Produces Analgesia by Inhibiting Tetrodotoxin-Resistant Nav1.8 Sodium Channel Activity in Rat Primary Sensory Neurons.
10.1007/s12264-021-00709-5
- Author:
Wei LIN
1
;
Wen-Wen ZHANG
1
;
Ning LYU
2
;
Hong CAO
1
;
Wen-Dong XU
3
;
Yu-Qiu ZHANG
4
Author Information
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 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. ninglu@fudan.edu.cn.
3. 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. wendongxu@fudan.edu.cn.
4. 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. yuqiuzhang@fudan.edu.cn.
- Publication Type:Journal Article
- Keywords:
Activin receptor-like kinase-2;
Dorsal root ganglion;
Growth differentiation factor-15;
Pain;
Tetrodotoxin-resistant sodium channel Nav1.8;
Whole-cell recording
- MeSH:
Analgesia;
Animals;
Ganglia, Spinal;
Growth Differentiation Factor 15;
NAV1.8 Voltage-Gated Sodium Channel;
Rats;
Sensory Receptor Cells;
Sodium Channels;
Tetrodotoxin/pharmacology*
- From:
Neuroscience Bulletin
2021;37(9):1289-1302
- CountryChina
- Language:English
-
Abstract:
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.
