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Pioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPARγ mechanisms.
- Source :
-
Pain [Pain] 2015 Mar; Vol. 156 (3), pp. 469-482. - Publication Year :
- 2015
-
Abstract
- Repeated administration of peroxisome proliferator-activated receptor gamma (PPARγ) agonists reduces neuropathic pain-like behavior and associated changes in glial activation in the spinal cord dorsal horn. As PPARγ is a nuclear receptor, sustained changes in gene expression are widely believed to be the mechanism of pain reduction. However, we recently reported that a single intrathecal (i.t.) injection of pioglitazone, a PPARγ agonist, reduced hyperalgesia within 30 minutes, a time frame that is typically less than that required for genomic mechanisms. To determine the very rapid antihyperalgesic actions of PPARγ activation, we administered pioglitazone to rats with spared nerve injury and evaluated hyperalgesia. Pioglitazone inhibited hyperalgesia within 5 minutes of injection, consistent with a nongenomic mechanism. Systemic or i.t. administration of GW9662, a PPARγ antagonist, inhibited the antihyperalgesic actions of intraperitoneal or i.t. pioglitazone, suggesting a spinal PPARγ-dependent mechanism. To further address the contribution of nongenomic mechanisms, we blocked new protein synthesis in the spinal cord with anisomycin. When coadministered intrathecally, anisomycin did not change pioglitazone antihyperalgesia at an early 7.5-minute time point, further supporting a rapid nongenomic mechanism. At later time points, anisomycin reduced pioglitazone antihyperalgesia, suggesting delayed recruitment of genomic mechanisms. Pioglitazone reduction of spared nerve injury-induced increases in GFAP expression occurred more rapidly than expected, within 60 minutes. We are the first to show that activation of spinal PPARγ rapidly reduces neuropathic pain independent of canonical genomic activity. We conclude that acute pioglitazone inhibits neuropathic pain in part by reducing astrocyte activation and through both genomic and nongenomic PPARγ mechanisms.
- Subjects :
- Analysis of Variance
Animal Diseases
Animals
Area Under Curve
Astrocytes metabolism
Capsaicin pharmacology
Glial Fibrillary Acidic Protein metabolism
Hyperalgesia drug therapy
Hyperalgesia etiology
Injections, Intraventricular
Male
Neuralgia complications
Neuralgia pathology
Nociception drug effects
Oncogene Proteins v-fos metabolism
Pain Threshold drug effects
Pioglitazone
Psychomotor Performance drug effects
Psychomotor Performance physiology
Rats
Rats, Sprague-Dawley
Spinal Cord Dorsal Horn metabolism
Spinal Cord Dorsal Horn pathology
Astrocytes drug effects
Hypoglycemic Agents therapeutic use
Neuralgia drug therapy
PPAR gamma metabolism
Thiazolidinediones therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1872-6623
- Volume :
- 156
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Pain
- Publication Type :
- Academic Journal
- Accession number :
- 25599238
- Full Text :
- https://doi.org/10.1097/01.j.pain.0000460333.79127.be