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)-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.
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.).
Takayuki
T
Saito
Maiko
M
Hasegawa-Moriyama
Tae
T
Kurimoto
Tomotsugu
T
Yamada
Eichi
E
Inada
Yuichi
Y
Kanmura
D000698:Analgesia / Q000379:methods; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000819:agonists*; D010149:Postoperative Pain / Q000150:complications / Q000188:drug therapy*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; C518399:resolvin D1; D000077154:Rosiglitazone; D004281:Docosahexaenoic Acids