Effect of Epac1 on pERK and VEGF Activation in Postoperative Persistent Pain in Rats.

The function of guanine nucleotide exchange protein conversion factor (Epac1) in regenerating nerves, stimulating insulin release, controlling vascular pressure, and controlling other metabolic activities has been recognized; however, few studies have addressed the potential role of Epac1 in controlling chronic postoperative pain. Using a rat model of skin/muscle incision and retraction (SMIR), our study tested the hypothesis that increased Epac1 signaling is a factor in postoperative chronic pain. Rats were randomly divided into normal, sham operation, SMIR, SMIR + Epac1 siRNA (Epac1 inhibitor), and normal + 8-pCPT (Epac1 agonist) groups. The mechanical withdrawal threshold (MWT) was used as an index of pain sensitivity. Epac1 expression in the incision-site muscle, DRG, and spinal cord was assessed using western blotting and immunofluorescence. The effects of Epac1 agonists and Epac1 siRNA on MWT and phosphorylated extracellular signal-regulated kinase (pERK), vascular endothelial growth factor (VEGF), protein release in the spinal cord, and DRG levels were also studied. SMIR increased Epac1 expression in the incision-site muscle, spinal cord, and DRG, and decreased MWT. 8-pCPT induced the development of hypersensitivity and increased pERK and VEGF expression in normal rats, whereas siRNA decreased the expression of pERK and VEGF. This study suggests that activation of the Epac1 signal might induce local postoperative recovery process, which could be an important mechanism by which to control postoperative chronic pain. Our data suggest that therapy targeted at decreasing Epac1 levels provides promise for the prevention and treatment of chronic postoperative pain.