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

AbstractAbstract Local administration of the peroxisome proliferator–activated receptor-γ agonist rosiglitazone attenuated incision-induced mechanical hyperalgesia through a resolvin D1–dependent mechanism in diabetic mice. Resolvin D1–mediated resolution of inflammation might be essential for peroxisome proliferator–activated receptor-γ–mediated analgesia associated with macrophage polarization to antiinflammatory M2 phenotype. Supplemental Digital Content is available in the text. 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)-γ agonists are used to treat diabetes, their postoperative analgesic effects in diabetes have not been evaluated. Methods The 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. 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 PPARγ-mediated analgesia during development of postincisional pain. Resolution of inflammation accelerated by RvD1 might promote PPARγ-mediated macrophage polarization to the M2 phenotype.