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Activation of peroxisome proliferator-activated receptor gamma in brain inhibits inflammatory pain, dorsal horn expression of Fos, and local edema.

Abstract：

:Systemic administration of thiazolidinediones reduces peripheral inflammation in vivo, presumably by acting at peroxisome proliferator-activated receptor gamma (PPARgamma) in peripheral tissues. Based on a rapidly growing body of literature indicating the CNS as a functional target of PPARgamma actions, we postulated that brain PPARgamma modulates peripheral edema and the processing of inflammatory pain signals in the dorsal horn of the spinal cord. To test this in the plantar carrageenan model of inflammatory pain, we measured paw edema, heat hyperalgesia, and dorsal horn expression of the immediate-early gene c-fos after intracerebroventricular (ICV) administration of PPARgamma ligands or vehicle. We found that ICV rosiglitazone (0.5-50 microg) or 15d-PGJ(2) (50-200 microg), but not vehicle, dose-dependently reduced paw thickness, paw volume and behavioral withdrawal responses to noxious heat. These anti-inflammatory and anti-hyperalgesia effects result from direct actions in the brain and not diffusion to other sites, because intraperitoneal and intrathecal administration of rosiglitazone (50 microg) and 15d-PGJ(2) (200 microg) had no effect. PPARgamma agonists changed neither overt behavior nor motor coordination, indicating that non-specific behavioral effects do not contribute to PPAR ligand-induced anti-hyperalgesia. ICV administration of structurally dissimilar PPARgamma antagonists (either GW9662 or BADGE) reversed the anti-inflammatory and anti-hyperalgesic actions of both rosiglitazone and 15d-PGJ(2). To evaluate the effects of PPARgamma agonists on a classic marker of noxious stimulus-evoked gene expression, we quantified Fos protein expression in the dorsal horn. The number of carrageenan-induced Fos-like immunoreactive profiles was less in rosiglitazone-treated rats as compared to vehicle controls. We conclude that pharmacological activation of PPARgamma in the brain rapidly inhibits local edema and the spinal transmission of noxious inflammatory signals.

journal_name

Neuropharmacology

journal_title

Neuropharmacology

authors

Morgenweck J,Abdel-Aleem OS,McNamara KC,Donahue RR,Badr MZ,Taylor BK

doi

10.1016/j.neuropharm.2009.10.008

subject

Has Abstract

pub_date

2010-02-01 00:00:00

pages

337-45

issue

eissn

0028-3908

issn

1873-7064

pii

S0028-3908(09)00339-6

journal_volume

pub_type

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Activation of peroxisome proliferator-activated receptor gamma in brain inhibits inflammatory pain, dorsal horn expression of Fos, and local edema.