title: The macrophage-mediated effects of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuate tactile allodynia in the early phase of neuropathic pain development.
abstract: BACKGROUND
  Neuroinflammation triggered by macrophage infiltration into sites of peripheral nerve injury may result in neuropathic pain. Peroxisome proliferator-activated receptor (PPAR)γ signaling regulates the properties of macrophages. However, the macrophage-mediated effects of PPARγ signaling on neuropathic pain triggered by peripheral inflammation have not been investigated.
  
  
  METHODS
  To evaluate the peripheral effects of PPARγ signaling on tactile allodynia, we administered the blood-brain barrier-impermeant PPARγ agonist, rosiglitazone, after partial sciatic nerve ligation (PSNL) as (1) systemic treatment during different phases of neuropathic pain development, (2) local injection to the PSNL site in the early phase, or (3) peritoneal macrophages pretreated with rosiglitazone transplanted into the PSNL site. In addition, the direct effect of rosiglitazone was evaluated in peritoneal macrophages activated with interferon-γ.
  
  
  RESULTS
  Systemic rosiglitazone treatment early in the course of progressive inflammation ameliorated tactile allodynia, macrophage infiltration, and production of proinflammatory mediators including cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloprotease 9 at the PSNL site. Local injection of rosiglitazone and transplantation of rosiglitazone-treated peritoneal macrophages at the ligation site significantly improved tactile allodynia. In peritoneal macrophages, rosiglitazone down-regulated interferon-γ-induced gene expression of cyclooxygenase-2 and inducible nitric oxide synthase and attenuated the chemotactic response to monocyte chemotactic protein-1.
  
  
  CONCLUSIONS
  Rosiglitazone treatment in the early phase of neuropathic pain significantly alleviated the development of tactile allodynia by regulating macrophage infiltration and production of proinflammatory molecules at the inflamed site. Our results indicate that the activation of PPARγ signaling in macrophages during the early phase may suppress neuropathic pain development.
authors.affiliation: Department of Anesthesiology and Pain Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Yoshika
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Maiko
authors.initials: M
authors.lastname: Hasegawa-Moriyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Eiichi
authors.initials: E
authors.lastname: Inada
mesh_terms: D000700:Analgesics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy*; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D008026:Ligation; D017737:Macrophages, Peritoneal / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000188:drug therapy*; D047495:PPAR gamma / Q000819:agonists*; D010812:Physical Stimulation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D012584:Sciatic Nerve / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone