Up-Regulation of ProBDNF/p75 Signaling in Spinal Cord Drives Inflammatory Pain in Male Rats.

BACKGROUND

The spinal cord expresses brain-derived neurotrophic factor precursor (proBDNF) and its receptor pan neurotrophin receptor 75 (p75). However, the role of spinal proBDNF signaling in the pathogenesis of inflammatory pain remains unknown.

METHODS

Rats were locally injected with complete Freund's adjuvant (CFA) to induce inflammatory pain. The proBDNF signal expression was detected by double-labeled immunofluorescence. ProBDNF protein, p75 extracellular domain (p75-ECD), or monoclonal anti-proBDNF (McAb-proB) were administrated by intrathecal injection to investigate their effects on pain behavior. Paw withdrawal thermal latency (PWL) and paw withdrawal mechanical threshold (PWT) were performed to evaluate pain behavior. Immunoblotting, immunohistochemistry, and immunofluorescence were used to assess inflammation-induced biochemical changes.

RESULTS

CFA induced a rapid increase in proBDNF in the ipsilateral spinal cord, and immunofluorescence revealed that CFA-enhanced proBDNF was expressed in NeuN positive neurons and GFAP positive astrocytes. The administration of furin cleavage-resistant proBDNF via intrathecal injection (.) significantly decreased the PWT and PWL, whereas McAb-proB by . alleviated CFA-induced pain-like hypersensitivity in rats. Meanwhile, CFA administration triggered the activation of p75 and its downstream signaling extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor (NF)-kappaB p65 in the spinal cord. . administration of p75-ECD suppressed CFA-induced pain and neuroinflammation, including the expression of p-ERK1/2, p-p65, and the gene expression of tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6).

CONCLUSION

Our study reveals that the activated proBDNF/p75signaling in the spinal cord contributes to the development of CFA-induced inflammatory pain. McAb-proB and p75-ECD appear to be promising therapeutic agents for inflammatory pain.