Role of bone morphogenetic protein-2/4 in astrocyte activation in neuropathic pain

BACKGROUND: Bone morphogenetic protein-2/4 (BMP2/4) has been recognized as promoters of astrocyte activity. Substantial evidence suggests that BMP2/4 may be elevated and plays a critical role in astrocyte activation upon spinal cord injury. Although neuropathic pain is similarly associated with astrocyte activation, the participation of BMP2/4 in this regard still remains unclear. METHODS: A rat model of neuropathic pain achieved by spinal nerve ligation at L5 was used to evaluate the expression of glial fibrillary acidic protein and BMP2/4 in the spinal cord in days 1, 4, 7, 10, and 14. Next, normal rats received intrathecal exogenous BMP2/4 and the antagonist Noggin to assess the effect of BMP2/4 on astrocyte activation. In both experiments, von Frey filaments were used to evaluate the changes in paw withdrawal threshold. In addition, Western blotting and immunofluorescence were performed to assess the expression of glial fibrillary acidic protein, BMP2/4, p-Smad 1/5/8, and phospho-signal transducer and activator of transcription-3 (p-STAT3) in the spinal cord. RESULTS: Firstly, spinal nerve ligation caused a significant increase in the expression of BMP4, while BMP2 levels remained unchanged. Secondly, exogenous BMP4 but not BMP2 induced a significant decrease in paw withdrawal threshold, along with the upregulation of glial fibrillary acidic protein. Moreover, exogenous BMP4 stimulated both p-Smad 1/5/8 and p-STAT3, while BMP2 only upregulated p-Smad 1/5/8. Finally, exogenous Noggin alleviated the decrease in paw withdrawal threshold induced by BMP4 and reduced astrocyte activation, as well as p-STAT3 upregulation. CONCLUSIONS: Our results indicate only BMP4—and not BMP2—intervened in allodynia in rats by eliciting glial activation probably through both p-Smad 1/5/8 and p-STAT3 signaling.