TY - JOUR
T1 - Intrathecal Rosiglitazone Acts at Peroxisome Proliferator-Activated Receptor-γ to Rapidly Inhibit Neuropathic Pain in Rats
AU - Churi, Sajay B.
AU - Abdel-Aleem, Omar S.
AU - Tumber, Kiranjeet K.
AU - Scuderi-Porter, Heather
AU - Taylor, Bradley K.
N1 - Funding Information:
Supported by National Institutes of Health grants DA10356, NS43383, and DA19656 (B.K.T.).
PY - 2008/7
Y1 - 2008/7
N2 - 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.
AB - 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.
KW - 16-deoxy-prostaglandin-J2
KW - Allodynia
KW - hyperalgesia
KW - pioglitazone
KW - rat
KW - spared nerve injury
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U2 - 10.1016/j.jpain.2008.02.002
DO - 10.1016/j.jpain.2008.02.002
M3 - Article
C2 - 18387855
AN - SCOPUS:45549087654
SN - 1526-5900
VL - 9
SP - 639
EP - 649
JO - Journal of Pain
JF - Journal of Pain
IS - 7
ER -