Research ReportDetailed characterization of neuro-immune responses following neuropathic injury in mice

Partial sciatic nerve injury is a common model of neuropathic pain in rodents, and produces both mechanical and thermal pain hypersensitivity. Several types of immune cells have been implicated in the pathogenesis of neuropathic pain due to nerve injury; however, the timing of their appearance has not been fully elucidated. Here, using immunohistochemistry, we characterized the time course and magnitude of inflammatory cell infiltration and resident immune cell activation in the sciatic nerves, L3-5 dorsal root ganglia (DRGs) and spinal segments following partial ligation of the sciatic nerve (PSNL) in C57BL/6J mice. PSNL markedly decreased paw withdrawal threshold to mechanical stimuli and paw withdrawal latency to thermal stimuli in the injured side. No changes were observed in the uninjured contralateral side. Mechanical allodynia persisted, and thermal hyperalgesia resolved by 2 weeks after injury. We found a significant increase in the numbers of infiltrating neutrophils, macrophages, dendritic cells and lymphocytes in the injured sciatic nerve and ipsilateral DRGs in comparison to sham-operated controls, with different timelines of recruitment for each cell type. Expression of ATF3 in the cell bodies of DRG neurons indicated about 30-40% neuronal damage. No neutrophils, dendritic cells, or lymphocytes were found in the spinal cord. However, a significant increase in the level of microglial and astrocytic activation was observed in the spinal dorsal horn and to a lesser extent in the ventral horn, peaking on days 7 and 14 after nerve injury. These changes corresponded with a significant increase in immunoreactivity for phosphorylated NR1 subunit of the NMDA receptor, and a significant decrease in IB4-labeled non-peptidergic nociceptive terminals in the ipsilateral dorsal horn. Our findings suggest differential roles for peripheral and central neuroimmune interactions in the production of neuropathic pain.

Research highlights► Partial ligation of the sciatic nerve in mice induces pain hypersensitivity. ► Infiltration of inflammatory cells to nervous tissues follows different time course. ► Nerve injury causes differential peripheral and central neuroimmune responses.