Suppression of WNK1-SPAK/OSR1 Attenuates Bone Cancer Pain by Regulating NKCC1 and KCC2.

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.

[Calculation of spectroscopic parameters of highly doped Er3+ in lithium niobate].

A highly doped Er3+: LiNbO3 (concentration 6 mol%) crystal was grown successfully by Czochralski method. The crystal is higher than that of the lowly doped Er3+ in LiNbO3 crystal, which is helpful to improve absorption coefficient of the grown the pumping efficiency. The absorption spectra at two unpolarized directions (X and Z) and two polarized directions (E parallel Z, E perpendicular Z) were measured. Using the Judd-Ofelt theory, and according to the measured absorption spectra, the intensity parameters omegalambda of Er3+ were fitted. The results of root-mean square (r. m. s) deviation show that the error of polarized fitting is less than that of unpolarized one. Thus fluorescence transition probabilities (Ajj), radioactive lifetime (tau), fluorescence branching ratio (beta), and integrated emission cross section (sigmap) were calculated and accepted according to the polarized results, and were also discussed and compared with the ones reported in the literature.