title: Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates inflammatory pain through the induction of heme oxygenase-1 in macrophages.
abstract: 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.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan. hase-mai@m3.kufm.kagoshima-u.ac.jp
authors.forename: Maiko
authors.initials: M
authors.lastname: Hasegawa-Moriyama
authors.forename: Tae
authors.initials: T
authors.lastname: Kurimoto
authors.forename: Mayo
authors.initials: M
authors.lastname: Nakama
authors.forename: Kohei
authors.initials: K
authors.lastname: Godai
authors.forename: Masayasu
authors.initials: M
authors.lastname: Kojima
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kuwaki
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kanmura
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000943:Antigens, Differentiation / Q000378:metabolism; D004002:Clodronic Acid; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005620:Freund's Adjuvant / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D037181:Lectins, C-Type / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D000943:Antigens, Differentiation; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D045162:Thiazolidinediones; C036763:monocyte-macrophage differentiation antigen; D000077154:Rosiglitazone; D004002:Clodronic Acid; D005620:Freund's Adjuvant; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1