Intrathecal rosiglitazone acts at peroxisome proliferator-activated receptor-gamma to rapidly inhibit neuropathic pain in rats.
In this report, we demonstrate the transcription, expression, and DNA-binding properties of the peroxisome proliferator-activated receptor (PPAR)-gamma 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-gamma decreases nerve injury-induced allodynia, we intrathecally administered PPAR-gamma 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-gamma agonist dose-dependently decreased mechanical and cold hypersensitivity. These effects were maximal at a dose of 100 microg and peaked at approximately 60 minutes after injection, a rapid time course suggestive of transcription-independent mechanisms of action. Concurrent administration of a PPAR-gamma 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-gamma agonists (100 microg) 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-gamma rapidly reverses nerve injury-induced mechanical allodynia. New or currently available drugs targeted at spinal PPAR-gamma may yield important therapeutic effects for the management of neuropathic pain.


CONCLUSIONS
PPAR-gamma receptor agonists such as rosiglitazone and pioglitazone are approved as insulin sensitizers by the United States Food and Drug Administration. We demonstrate PPAR-gamma expression in the spinal cord and report that activation of these receptors inhibits allodynia. BBB-permeant PPAR-gamma agonists may yield important therapeutic effects for the management of neuropathic pain.
Churi
Sajay B
SB
Department of Pharmacology, School of Medicine, Tulane University, New Orleans, Louisiana, USA.
Abdel-Aleem
Omar S
OS
Tumber
Kiranjeet K
KK
Scuderi-Porter
Heather
H
Taylor
Bradley K
BK
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001559:Benzhydryl Compounds; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009437:Neuralgia / Q000503:physiopathology / Q000517:prevention & control*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D012584:Sciatic Nerve / Q000293:injuries / Q000503:physiopathology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D004852:Epoxy Compounds; D047495:PPAR gamma; D015230:Prostaglandin D2; D000077154:Rosiglitazone; D045162:Thiazolidinediones; C037112:9-deoxy-delta-9-prostaglandin D2; C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds