Resolution of Inflammation by Resolvin D1 Is Essential for Peroxisome Proliferator-activated Receptor-γ-mediated Analgesia during Postincisional Pain Development in Type 2 Diabetes

Background: The 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)- agonists are used to treat diabetes, their postoperative analgesic effects in diabetes have not been evaluated. Methods: The PPAR 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. Results: Rosiglitazone 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. Conclusions: In diabetes, exogenous administration of RvD1 is essential for PPAR-mediated analgesia during development of postincisional pain. Resolution of inflammation accelerated by RvD1 might promote PPAR-mediated macrophage polarization to the M2 phenotype.