Propofol attenuates postoperative hyperalgesia via regulating spinal GluN2B‐p38MAPK/EPAC1 pathway in an animal model of postoperative pain

Abstract Background Total intravenous anesthesia with propofol has been shown to reduce postoperative pain in some clinical studies, but knowledge of its underlying analgesic mechanism remains limited. In this study, we compared the analgesic effects of propofol versus isoflurane in an animal model of postoperative pain and evaluated its underlying molecular mechanisms. Methods Plantar incision was made in the hind paws of rats under general anesthesia with 2.5% of inhalational isoflurane (isoflurane group) or intravenous infusion of propofol (1.5 mg kg −1 min −1 , propofol group). Mechanical allodynia was assessed by paw withdrawal threshold before and after incision. Spinal dorsal horns (L3–L5) were harvested 1 hr after incision to assess the level of phosphorylated GluN2B, p38MAPK, ERK, JNK, and EPAC using Western blot and immunofluorescence. Results Mechanical allodynia induced by plantar incision peaked at 1 hr and lasted for 3 days after incision. It was significantly less in the propofol group compared with the isoflurane group in the first 2 hr following incision. The incision‐induced increases in phosphorylated GluN2B, p38MAPK, and EPAC1 were significantly reduced in the propofol group. The number of spinal dorsal neurons co‐expressed with EPAC1 and c‐Fos after the incision was significantly lower in the propofol group. Conclusion Propofol reduced pain responses in an animal model of postoperative pain and suppressed the spinal GluN2B‐p38MAPK/EPAC1 signaling pathway. Since the p38MAPK/EPAC pathway plays a critical role in the development of postoperative hyperalgesia, our results provide evidence‐based behavioral, molecular, and cellular mechanisms for the analgesic effects of propofol when used for general anesthesia. Significance These findings may provide a new mechanism for the postsurgical analgesic effect of propofol, which is particularly interesting during the subacute period after surgery as it is the critical period for the development of persistent postsurgical pain.