PPARg activation blocks development and reduces established neuropathic pain in rats

Peroxisomeproliferator-activated receptorgamma(PPARg) is emergingasanewpharmacotherapeutic target for chronic pain.When oral (3e30mg/kg/day in chow for 7 wk) or twice-daily intraperitoneal (1e10mg/kg/ day for 2 wk) administration began before spared nerve injury (SNI), pioglitazone, a PPARg agonist, dosedependently prevented multiple behavioral signs of somatosensory hypersensitivity. The highest dose of intraperitoneal pioglitazone did not produce ataxia or reductions in transient mechanical and heat nociception, indicating that inhibitory effects on hypersensitivity were not secondary to adverse drug-induced behaviors or antinociception. Inhibitory effects on hypersensitivity persisted at least one week beyond cessation of pioglitazone administration, suggestive of long-lasting effects on gene expression. Blockade of PPARg with GW9662, an irreversible and selective PPARg antagonist, dose-dependently reduced the inhibitory effect of pioglitazone on hypersensitivity, indicating a PPARg-dependent action. Remarkably, a single preemptive injection of pioglitazone 15 min before SNI attenuated hypersensitivity for at least 2 weeks; thiswas enhancedwith a second injectiondelivered12h after SNI. Pioglitazone injections beginning after SNI also reduced hypersensitivity, albeit to a lesser degree than preemptive treatment. Intraperitoneal pioglitazone significantly reduced the nerve injury-induced up-regulation of cd11b, GFAP, and p-p38 in the dorsal horn, indicating a mechanism of action involving spinal microglia and/or astrocyte activation. Oral pioglitazone significantly reduced touch stimulus-evoked phospho-extracellular signal-related kinase (p-ERK) in lamina IeII, indicating a mechanism of action involving inhibition of central sensitization. We conclude that pioglitazone reduces spinal glial and stimulus-evoked p-ERK activation and that PPARg activation blocks the development of and reduces established neuropathic pain. 2013 Elsevier Ltd. All rights reserved.