The most common complaint after surgery is postsurgical pain. Generally, this was considered to resolve after a recovery period. However, persistent pain after surgery, so-called chronic postsurgical pain (CPSP), is now recognized as a critical problem. To elucidate the factors that contribute to CPSP, we developed a new mouse model of persistent postoperative pain induced by electrocautery and investigated the molecular mechanism of the development of CPSP. Acute hyperalgesia was observed with both incision and electrocautery, whereas persistent hyperalgesia was only observed after electrocautery. Consistent with behavioral data, electrocautery treatment induced long-lasting neuronal activation related to synaptic plasticity and potently increased mRNA levels of the key modulators of neuropathic pain in the spinal cord, compared to incision. Furthermore, we found that the overexpression of these genes was observed almost exclusively in CPSP-activated neurons associated with epigenetic modifications. These findings suggest that electrocautery-associated invasion contributes to CPSP along with epigenetic modification. We are currently investigating the possible changes in brain function caused by electrocautery.