• Takayuki Saito, Maiko Hasegawa-Moriyama, Tae Kurimoto, Tomotsugu Yamada, Eichi Inada, and Yuichi Kanmura.
• From the Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan (T.S., M.H.-M., T.K., T.Y., Y.K.); and Department of Anesthesiology and Pain Medicine, Juntendo University School of Medicine, Tokyo, Japan (T.S., E.I.).
• Anesthesiology. 2015 Dec 1;123(6):1420-34.

BackgroundThe wound healing process following acute inflammation after surgery is impaired in diabetes. Altered macrophage functions are linked to delayed tissue repair and pain development in diabetes. Although peroxisome proliferator-activated receptor (PPAR)-γ agonists are used to treat diabetes, their postoperative analgesic effects in diabetes have not been evaluated.MethodsThe PPARγ agonist rosiglitazone (rosi) was injected at the incision site of diabetic (db/db) mice with resolvin (Rv) D1, a lipid mediator involved in resolution of inflammation. Pain-related behavior, neutrophil infiltration, phagocytosis, and macrophage polarity were assessed for 7 days postoperatively.ResultsRosiglitazone and RvD1 alleviated mechanical hyperalgesia in db/db (db) mice, whereas rosiglitazone alone did not alter mechanical thresholds on days 4 (db rosi + RvD1 vs. db rosi: 0.506 ± 0.106 vs. 0.068 ± 0.12) and 7 (0.529 ± 0.184 vs. 0.153 ± 0.183) after incision (n = 10 per group). In control m/m mice, the rosiglitazone-induced analgesic effects were reversed by knockdown with arachidonate 5-lipoxygenase small interfering RNA, but these were restored by addition of RvD1. In db/db mice treated with rosiglitazone and RvD1, local infiltration of neutrophils was markedly reduced, with an associated decrease in total TdT-mediated dUTP nick-end labeling cells. Acceleration of rosiglitazone-induced phenotype conversion of infiltrated macrophages from M1 to M2 was impaired in db/db mice, but it was effectively restored by RvD1 in db/db wounds.ConclusionsIn diabetes, exogenous administration of RvD1 is essential for PPARγ-mediated analgesia during development of postincisional pain. Resolution of inflammation accelerated by RvD1 might promote PPARγ-mediated macrophage polarization to the M2 phenotype.

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