Highlights
- •WNK1 was upregulated in the bone cancer pain (BCP) rat model.
- •WNK1-SPAK/OSR1-NKCC1/KCC2 signaling contributed to BCP in rats.
- •Intrathecal WNK1 siRNA or closantel attenuated pain behavior of BCP rats.
- •The WNK1 pathway may be a potential therapeutic target for BCP.
Abstract
Our preliminary experiment indicated the activation of with-nolysine kinases 1 (WNK1)
in bone cancer pain (BCP) rats. This study aimed to investigate the underlying mechanisms
via which WNK1 contributed to BCP. A rat model of BCP was induced by Walker-256 tumor
cell implantation. WNK1 expression and distribution in the lumbar spinal cord dorsal
horn and dorsal root ganglion were examined. SPS1-related proline/alanine-rich kinase
(SPAK), oxidative stress-responsive kinase 1 (OSR1), sodium-potassium-chloride cotransporter
1 (NKCC1), and potassium-chloride cotransporter 2 (KCC2) expression were assessed.
Pain behaviors including mechanical allodynia and movement-evoked pain were measured.
BCP rats exhibited significant mechanical allodynia, with increased WNK1 expression
in the dorsal horn and dorsal root ganglion neurons, elevated SPAK/OSR1 and NKCC1
expression in the dorsal root ganglion, and decreased KCC2 expression in the dorsal
horn. WNK1 knock-down by small interfering alleviated mechanical allodynia and movement-evoked
pain, inhibited WNK1-SPAK/OSR1-NKCC1 activities, and restored KCC2 expression. In
addition, closantel (a WNK1-SPAK/OSR1 inhibitor) improved pain behaviors, downregulated
SPAK/OSR1 and NKCC1 expression, and upregulated KCC2 expression in BCP rats. Activation
of WNK1-SPAK/OSR1 signaling contributed to BCP in rats by modulating NKCC1 and KCC2
expression. Therefore, suppression of WNK1-SPAK/OSR1 may serve as a potential target
for BCP therapy.
Perspective
Our findings demonstrated that the WNK1-SPAK/OSR1 signaling contributed to BCP in
rats via regulating NKCC1 and KCC2. Suppressing this pathway reduced pain behaviors.
Based on these findings, the WNK1-SPAK/OSR1 signaling may be a potential target for
BCP therapy.
Key words
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Article info
Publication history
Published online: May 11, 2019
Accepted:
May 7,
2019
Received in revised form:
April 15,
2019
Received:
October 10,
2018
Footnotes
J.G., K.P., and M.S. contributed equally.
The study was supported by the National Science Foundation of China (No. 81471136 and 81601659). All authors declared there were no conflict of interests involved.
Supplementary data accompanying this article are available online at www.jpain.org and www.sciencedirect.com.
Identification
Copyright
© 2019 by the American Pain Society
