CXCL12/CXCR4 signaling-mediated ERK1/2 activation in spinal cord contributes to the pathogenesis of postsurgical pain in rats

BACKGROUND: It has been demonstrated that upregulation of CXCL12 and CXCR4 in spinal cord involves in the pathogenesis of neuropathic, inflammatory, and cancer pain. However, whether CXCL12/CXCR4 signaling contributes to postsurgical pain remains unknown. The aim of the present study is to investigate the role of CXCL12/CXCR4 signaling in the genesis of postsurgical pain and the underlying mechanism. RESULTS: Plantar incision in rat hind paw resulted in increased expressions of CXCL12 and CXCR4 in spinal dorsal horn. Double immunofluorescence staining revealed that CXCL12 expressed in neurons and astrocytes, and CXCR4 exclusively co-localized with neuronal cells. Prior administration of AMD3100, a specific antagonist of CXCR4, or CXCL12 neutralizing antibody, intrathecally attenuated plantar incision-induced mechanical allodynia and thermal hyperalgesia. Plantar incision also augmented the phosphorylation of NF-κB p65 in spinal cord. Pre intrathecal (i.t.) injection of PDTC, a specific NF-κB activation inhibitor, alleviated plantar incision-induced postsurgical pain and reduced the expression of CXCL12 in spinal cord. Correlated with the upregulation of CXCL12 and CXCR4, plantar incision also resulted in an increased phosphorylation of extracellular signal-regulated kinase 1/2 and Akt in spinal cord. Prior i.t. administration of AMD3100 prevented extracellular signal-regulated kinase, but not Akt, activation in spinal cord. Rats when given a repetitive i.t. PD98059, a specific extracellular signal-regulated kinase inhibitor, started 30 min before surgery also ameliorate plantar incision-induced mechanical and thermal pain hypersensitivity. CONCLUSION: Our results suggests that plantar incision-induced activation of NF-κB signaling may mediate upregulation of CXCL12 in spinal cord, and CXCL12/CXCR4 signaling via extracellular signal-regulated kinase activation contributes to the genesis of postsurgical pain.