Involvement of NF-κB and the CX3CR1 Signaling Network in Mechanical Allodynia Induced by Tetanic Sciatic Stimulation / 神经科学通报·英文版

Tetanic stimulation of the sciatic nerve (TSS) triggers long-term potentiation in the dorsal horn of the spinal cord and long-lasting pain hypersensitivity. CX3CL1-CX3CR1 signaling is an important pathway in neuronal-microglial activation. Nuclear factor κB (NF-κB) is a key signal transduction molecule that regulates neuroinflammation and neuropathic pain. Here, we set out to determine whether and how NF-κB and CX3CR1 are involved in the mechanism underlying the pathological changes induced by TSS. After unilateral TSS, significant bilateral mechanical allodynia was induced, as assessed by the von Frey test. The expression of phosphorylated NF-κB (pNF-κB) and CX3CR1 was significantly up-regulated in the bilateral dorsal horn. Immunofluorescence staining demonstrated that pNF-κB and NeuN co-existed, implying that the NF-κB pathway is predominantly activated in neurons following TSS. Administration of either the NF-κB inhibitor ammonium pyrrolidine dithiocarbamate or a CX3CR1-neutralizing antibody blocked the development and maintenance of neuropathic pain. In addition, blockade of NF-κB down-regulated the expression of CX3CL1-CX3CR1 signaling, and conversely the CX3CR1-neutralizing antibody also down-regulated pNF-κB. These findings suggest an involvement of NF-κB and the CX3CR1 signaling network in the development and maintenance of TSS-induced mechanical allodynia. Our work suggests the potential clinical application of NF-κB inhibitors or CX3CR1-neutralizing antibodies in treating pathological pain.

Involvement of peripheral NFκB in tetanic sciatic stimulation-induced neuropathic pain / 生理学报

Tetanic stimulation of the sciatic nerve (TSS) induces long-term potentiation (LTP) of both C- and A-fiber-evoked field potentials in the spinal dorsal horn and long-lasting mechanical allodynia in rats. Though central mechanisms underlying those phenomena have been well studied, peripheral mechanisms still remain poorly known. Nuclear factor kappa B (NFκB) is an important transcription factor. In the spinal cord, NFκB plays a key role in regulating the expression of numerous pro-inflammation factors and contributes to glial activation in central nervous system, suggesting the involvement of spinal NFκB in central sensitization. To address whether NFκB in the dorsal root ganglion (DRG) participates in peripheral sensitization, we examined NFκB expression in the DRG and the effect of inhibiting NFκB activation on neuropathic pain using behavior test, Western blot analysis and immunohistochemical approaches. The results showed that TSS induced long-lasting mechanical allodynia in bilateral hind paws and increased phospho-NFκB expression in the bilateral DRG. The activated NFκB mainly expressed in nuclei not only of neurons, but also of Schwann cells and satellite glial cells. Moreover, NFκB inhibitor pyrrolidine dithiocarbamate (PDTC) significantly alleviated TSS-induced allodynia. Our results suggest that peripheral NFκB may be involved in TSS-induced neuropathic pain, and provide new evidence for the peripheral mechanism of 'mirror pain'.