Spinal SIRP伪1-SHP2 interaction regulates spinal nerve ligation-induced neuropathic pain via PSD-95-dependent NR2B activation in rats
- 作者：Hsien-Yu Peng<sup>asup><sup> ; sup><sup>bsup> ; Gin-Den Chen<sup>csup> ; Cheng-Yuang Lai<sup>dsup><sup> ; sup><sup>esup> ; Ming-Chun Hsieh<sup>dsup><sup> ; sup><sup>esup> ; Tzer-Bin Lin<sup>bsup><sup> ; sup><sup>dsup><sup> ; sup><sup>fsup><sup> ; sup><sup>tblin2@gmail.comsup>
- 关键词：Spinal nerve ligation ; SIRP伪1 ; SHP2 ; PSD-95 ; NMDA ; NR2B ; NSC-87877
- 刊名：Pain
- 出版年：2012
- 期刊代码：214_03043959
- 类别：med
- 出版时间：May, 2012
- 卷：153
- 期：5
- 页码：1042-1053
- 文件大小：1684 K
摘要
The fact that neuropathic pain mechanisms are not well understood is a major impediment in the development of effective clinical treatments. We examined whether the interaction between signal regulatory protein alpha 1 (SIRP伪1) and Src homology-2 domain-containing protein tyrosine phosphatase 2 (SHP2), and the downstream spinal SHP2/postsynaptic density 95 (PSD-95)/N-methyl-d-aspartate receptor NR2B subunit signaling cascade play a role in neuropathic pain. Following spinal nerve ligation (L5), we assessed tactile allodynia using the von Frey filament test and analyzed dorsal horn samples (L4-5) by Western blotting, reverse transcription polymerase chain reaction, coimmunoprecipitation, and immunofluorescence. Nerve ligation induced allodynia, SIRP伪1, SHP2, phosphorylated SHP2 (pSHP2), and phosphorylated NR2B (pNR2B) expression, and SHP2-PSD-95, pSHP2-PSD-95, PSD-95-NR2B, and PSD-95-pNR2B coimmunoprecipitation in the ipsilateral dorsal horn. In allodynic rats, injury-induced SHP2 immunoreactivity was localized in the ipsilateral dorsal horn neurons and coincident with PSD-95 and NR2B immunoreactivity. SIRP伪1 silencing using small interfering RNA (siRNA; 1, 3, or 5 渭g/rat for 7 days) prevented injury-induced allodynia and the associated changes in protein expression, phosphorylation, and coimmunoprecipitation. Intrathecal administration of NSC-87877 (an SHP2 antagonist; 1, 10, or 100 渭M/rat) and SIRP伪1-neutralizing antibodies (1, 10, or 30 渭g/rat) suppressed spinal nerve ligation-induced allodynia, spinal SHP2 and NR2B phosphorylation, and SHP2/phosphorylated SHP2-PSD-95 and PSD-95-NR2B/phosphorylated NR2B coprecipitation. SHP2 siRNA led to similar effects as the NSC-87877 and SIRP伪1 antibody treatments, except it prevented the allodynia-associated spinal SHP2 expression. In conclusion, our results suggest that a spinal SIRP伪1-SHP2 interaction exists that subsequently triggers SHP2/PSD-95/NR2B signaling, thereby playing a role in neuropathic pain development.