Intrathecal Rosiglitazone Acts at Peroxisome Proliferator-Activated Receptor-γ to Rapidly Inhibit Neuropathic Pain in Rats

Sajay B. Churi, Omar S. Abdel-Aleem, Kiranjeet K. Tumber, Heather Scuderi-Porter, Bradley K. Taylor

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

In this report, we demonstrate the transcription, expression, and DNA-binding properties of the peroxisome proliferator-activated receptor (PPAR)-γ subtype of the peroxisome proliferator-activated nuclear receptor family to the spinal cord with real-time PCR, Western blot, and electrophoretic mobility shift assay. To test the hypothesis that activation of spinal PPAR-γ decreases nerve injury-induced allodynia, we intrathecally administered PPAR-γ agonists and/or antagonists in rats after transection of the tibial and common peroneal branches of the sciatic nerve. Single injection of either a natural (15-deoxy-prostaglandin J2, 15d-PGJ2) or synthetic (rosiglitazone) PPAR-γ agonist dose-dependently decreased mechanical and cold hypersensitivity. These effects were maximal at a dose of 100 μg and peaked at ∼60 minutes after injection, a rapid time course suggestive of transcription-independent mechanisms of action. Concurrent administration of a PPAR-γ antagonist (bisphenol A diglycidyl ether, BADGE) reversed the effects of 15d-PGJ2 and rosiglitazone, further indicating a receptor-mediated effect. In animals without nerve injury, rosiglitazone did not alter motor coordination, von Frey threshold, or withdrawal response to a cool stimulus. Intraperitoneal and intracerebroventricular administration of PPAR-γ agonists (100 μg) did not decrease mechanical and cold hypersensitivity, arguing against effects subsequent to diffusion from the intrathecal space. We conclude that ligand-induced activation of spinal PPAR-γ rapidly reverses nerve injury-induced mechanical allodynia. New or currently available drugs targeted at spinal PPAR-γ may yield important therapeutic effects for the management of neuropathic pain. Perspective: PPAR-γ receptor agonists such as rosiglitazone and pioglitazone are approved as insulin sensitizers by the United States Food and Drug Administration. We demonstrate PPAR-γ expression in the spinal cord and report that activation of these receptors inhibits allodynia. BBB-permeant PPAR-γ agonists may yield important therapeutic effects for the management of neuropathic pain.

Original languageEnglish (US)
Pages (from-to)639-649
Number of pages11
JournalJournal of Pain
Volume9
Issue number7
DOIs
StatePublished - Jul 2008

Bibliographical note

Funding Information:
Supported by National Institutes of Health grants DA10356, NS43383, and DA19656 (B.K.T.).

Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.

Keywords

  • 16-deoxy-prostaglandin-J2
  • Allodynia
  • hyperalgesia
  • pioglitazone
  • rat
  • spared nerve injury

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