Peroxisome proliferator-activated receptor-gamma agonist... : PAIN (original) (raw)

Article

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

Hasegawa-Moriyama, Maikoa,*; Kurimoto, Taea; Nakama, Mayoa; Godai, Koheia; Kojima, Masayasub; Kuwaki, Tomoyukic; Kanmura, Yuichia

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

a_Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan_

b_Department of Molecular Genetics, Institute of Life Sciences, Kurume University, Kurume, Fukuoka 839-0864, Japan_

c_Department of Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan_

*Corresponding author. Address: Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. Tel.: +81 99 275 5430; fax: +81 99 265 1642.

E-mail address: [email protected]

Submitted December 14, 2012; revised April 10, 2013; accepted April 17, 2013.

Abstract

Activation of PPARγ signaling in macrophages promotes differentiation of macrophages to M2 phenotype. PPARγ agonist rosiglitazone attenuated CFA-induced inflammatory pain by a PPARγ/HO-1-dependent pathway in macrophages.

Macrophage infiltration to inflammatory sites promotes tissue repair and may be involved in pain hypersensitivity. Peroxisome proliferator-activated receptor (PPAR)γ 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 PPARγ 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 PPARγ signaling, promotes differentiation of macrophages to M2 phenotype. In this study, we investigated how rosiglitazone alters pain hypersensitivity by a PPARγHO-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-γ. 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 PPARγ/HO-1-dependent mechanism. PPARγ signaling in macrophages may be a potential therapeutic target for the treatment of acute pain development.