Involvement of acute postoperative pain on the development of neuroinflammation and related memory deficits in rats
Daiki Yamanaka, Takashi Kawano, Masataka Yokoyama
Introduction: Postoperative delirium (POD) is a common but serious complication characterized by an acute disturbance in attention and cognition. Previous clinical studies identified that acute postoperative pain may contribute to the development of POD, whereas supportive laboratory evidence of this association is currently lacking. Although the exact mechanism remains unclear, recent empirical data suggest that neuroinflammation plays a key role in POD development. In the present study, we investigated the effect of acute postoperative pain on neuroinflammation and related delirium-like behavior after surgery in rats.
Material and Methods: All experimental procedures were approved by the Institutional Animal Care and Use Committee of the Kochi Medical School. Male Wister rats (2-4 months old) were randomly allocated to one of three groups containing 8 rats each: isoflurane anesthesia without surgery (Group C); isoflurane anesthesia with laparotomy (Group S); and isoflurane anesthesia with laparotomy plus a wound infiltration with 0.2% ropivacaine (300 µl) after surgery (Group S+R). In surgical groups, animals underwent a 2-cm midline incision as a laparotomy model. During the laparotomy, 10 cm of the small intestine was exteriorized, and then manipulated with fingers for 3 min. Tissue adhesive glue was also used to ensure closure of the skin incision. Acute postoperative pain was assessed by the facial expressions using rat grimace scale (RGS; Molecular Pain 2011, 7:55). The animals in all groups were assessed for cognitive function using a trace fear conditioning task 2-days after surgery or sham procedure. After the completion of the cognitive testing, the hippocampus and medial prefrontal cortex (mPFC) were dissected for measurement of IL-1β by enzyme-linked immunosorbent assay. Differences between the data sets were evaluated by performing repeated-measure one-way analysis of variance test, followed by Bonferroni post hoc tests. Results with p<0.05 were considered statistically significant.
Results: In Group C, RGS pain score after emergence from anesthesia (0.21 ± 0.07) was comparable to preoperative baseline (0.18 ± 0.04). In group S, a significant increase in RGS pain score from baseline was observed until 6 h after emergence from anesthesia (maximum 1.26 ± 0.41 at 2h after emergence from anesthesia). However, in Group S+R, postoperative increase in RGS pain score was not observed, indicating the successful postoperative pain management in this group. During the training session in the trace fear conditioning task, no group differed in their freezing responses. On the other hand, during trace memory retention session, rats in Group S froze significantly less than animals in Group C. This surgery induced cognitive impairment was not observed in Group S+R. The average IL-1β levels in both hippocampus and mPFC of Group S were significantly greater than those of Group C. However, the IL-1β levels in both regions of Group S+R were comparable with those in Group C.
Conclusion: The results of our proof-of-concept study indicated that acute postoperative pain may contribute to the development of acute neuroinflammation and related memory deficits after abdominal surgery in rats. Our finding implies that postoperative pain management may be one of the most important factor for prevention of POD.