Emerging evidence indicates that CXCL12/ CXCR4 signaling is involved in chronic pain. However, few studies have systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mech- a...Emerging evidence indicates that CXCL12/ CXCR4 signaling is involved in chronic pain. However, few studies have systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mech- anism. Here, we determined that spared nerve injury （SNI） increased the expression of CXCL12 and its cognate receptor CXCR4 in lumbar 5 dorsal root ganglia （DRG） neurons and satellite glial cells. SNI also induced long- lasting upregulation of CXCL12 and CXCR4 in the ipsi- lateral L4-5 spinal cord dorsal horn, characterized by CXCL12 expression in neurons and microglia, and CXCR4 expression in neurons and astrocytes. Moreover, SNI- induced a sustained increase in TNF-α expression in the DRG and spinal cord. Intraperitoneal injection （i.p.） of the TNF-α synthesis inhibitor thalidomide reduced the SNI-in- duced mechanical hypersensitivity and inhibited the expression of CXCL12 in the DRG and spinal cord. Intrathecal injection （i.t.） of the CXCR4 antagonist AMD3100, both 30 rain before and 7 days after SNI, reduced the behavioral signs of allodynia. Rats given an i.t. or i.p. bolus of AMD3100 on day 8 of SNI exhibited attenuated abnormal pain behaviors. The neuropathic pain established following SNI was also impaired by i.t. admin- istration of a CXCL12-neutralizing antibody. Moreover, repetitive i.t. AMD3100 administration prevented the acti- vation of ERK in the spinal cord. The mechanical hyper- sensitivity induced in nai＇ve rats by i.t. CXCL12 was alleviated by pretreatment with the MEK inhibitor PD98059. Collectively, our results revealed that TNF-α might mediate the upregulation of CXCL12 in the DRG and spinal cord following SNI, and that CXCL 12/CXCR4 sig- naling via ERK activation contributes to the development and maintenance of neuropathic pain.展开更多
基金supported by grants from the National Natural Science Foundation of China(31171070,81171060,81501070and 81571079)
文摘Emerging evidence indicates that CXCL12/ CXCR4 signaling is involved in chronic pain. However, few studies have systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mech- anism. Here, we determined that spared nerve injury （SNI） increased the expression of CXCL12 and its cognate receptor CXCR4 in lumbar 5 dorsal root ganglia （DRG） neurons and satellite glial cells. SNI also induced long- lasting upregulation of CXCL12 and CXCR4 in the ipsi- lateral L4-5 spinal cord dorsal horn, characterized by CXCL12 expression in neurons and microglia, and CXCR4 expression in neurons and astrocytes. Moreover, SNI- induced a sustained increase in TNF-α expression in the DRG and spinal cord. Intraperitoneal injection （i.p.） of the TNF-α synthesis inhibitor thalidomide reduced the SNI-in- duced mechanical hypersensitivity and inhibited the expression of CXCL12 in the DRG and spinal cord. Intrathecal injection （i.t.） of the CXCR4 antagonist AMD3100, both 30 rain before and 7 days after SNI, reduced the behavioral signs of allodynia. Rats given an i.t. or i.p. bolus of AMD3100 on day 8 of SNI exhibited attenuated abnormal pain behaviors. The neuropathic pain established following SNI was also impaired by i.t. admin- istration of a CXCL12-neutralizing antibody. Moreover, repetitive i.t. AMD3100 administration prevented the acti- vation of ERK in the spinal cord. The mechanical hyper- sensitivity induced in nai＇ve rats by i.t. CXCL12 was alleviated by pretreatment with the MEK inhibitor PD98059. Collectively, our results revealed that TNF-α might mediate the upregulation of CXCL12 in the DRG and spinal cord following SNI, and that CXCL 12/CXCR4 sig- naling via ERK activation contributes to the development and maintenance of neuropathic pain.
