Pioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPAR-γ mechanisms

Repeated administration of peroxisome proliferator activated receptor gamma (PPAR gamma) agonists reduces neuropathic pain-like behavior and associated changes in glial activation in the spinal cord dorsal horn. As PPAR gamma 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 PPAR gamma agonist, reduced hyperalgesia within 30 minutes, atime frame that is typically less than that required for genomic mechanisms. To determine the very rapid antihyperalgesic actions of PPAR gamma 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 it. administration of GW9662, a PPAR gamma antagonist, inhibited the antihyperalgesic actions of intraperitoneal or it. pioglitazone, suggesting a spinal PPART-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 PPAR gamma 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 PPAR gamma mechanisms.