Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates inflammatory pain through the induction of heme oxygenase-1 in macrophages

Macrophage infiltration to inflammatory sites promotes tissue repair and may be involved in pain hypersensitivity. Peroxisome proliferator-activated receptor (PPAR)gamma signaling is known to regulate polarity of macrophages, which are often referred to as proinflammatory (M1) and antiinflammatory (M2) macrophages. We recently showed that the PPAR gamma agonist rosiglitazone ameliorated the development of postincisional hyperalgesia by increasing the influx of M2 macrophages to inflamed sites. It has been suggested that heme oxygenase (HO)-1, upregulated by PPAR gamma signaling, promotes differentiation of macrophages to M2 phenotype. In this study, we investigated how rosiglitazone alters pain hypersensitivity by a PPAR gamma HO-1-dependent mechanism during the course of inflammation induced by complete Freund's adjuvant. Local administration of rosiglitazone alleviated mechanical hyperalgesia, with increased gene induction of HO-1. Phenotype switching of infiltrated macrophages to M2 by rosiglitazone was reversed by an HO-1 inhibitor, tin protoporphyrin, at the inflamed sites. Direct stimulation of peritoneal macrophages with rosiglitazone also increased HO-1 induction in the presence of lipopolysaccharide/interferon-gamma. Moreover, rosiglitazone increased gene induction of endogenous opioid proenkephalin, both at inflamed sites and in isolated macrophages. Administration of naloxone blocked the analgesic effects of rosiglitazone. We speculate that rosiglitazone alleviated the development of inflammatory pain, possibly through regulating the M1/M2 balance at the inflamed site by a PPAR gamma/HO-1-dependent mechanism. PPAR gamma signaling in macrophages may be a potential therapeutic target for the treatment of acute pain development. (C) 2013 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.