The gamma subtype of the peroxisome proliferator-activated receptor family (PPAR γ) is a nuclear receptor that regulates gene transcription. Because recent immunohistochemical studies indicate that PPAR γ are found in the dorsal horn of the spinal cord, we tested the hypothesis that activation of spinal PPAR γ will decrease behavioral signs of neuropathic pain. To address this question, male Sprague-Dawley rats were anesthetized with isoflurane, spared nerve injury (SNI) surgery was performed, and the rats were instrumented with intrathecal catheters. After 7 d, allowing full development of behavioral signs of mechanical allodynia (von Frey filament test) and cold allodynia (acetone test), we administered either saline, 15dPGJ2 (PPAR γ receptor agonist) or rosiglitazone (PPAR γ receptor agonist) in a randomized protocol, and re-evaluated allodynia at 30, 60, 90, 120, and 240 min. We found that 15dPGJ2 dose-dependently decreased mechanical allodynia and rosiglitazone dose-dependently decreased mechanical and cold allodynia. The anti-allodynic effect of 15dPGJ2 and rosiglitazone peaked at 30-60 min and at 60-90 min, respectively, and lasted less than 4 h. The concurrent administration of BADGE (a PPAR γ receptor antagonist) reduced the anti-allodynic effects of 15dPGJ2 and rosiglitazone, indicating a receptor-mediated effect. There was no alteration of motor coordination as assessed with a rotarod. To evaluate for opiate-like tolerance, rosiglitazone was administered chronically (2 intrathecal injections of rosiglitazone per day, administered 8 h apart). Rosiglitazone equally reduced mechanical allodynia in the SNI animal after 5 d of treatment as after single administration. Cold allodynia was more effectively reduced after 5 d of treatment than after single administration. We conclude that activation of spinal PPAR γ reverses mechanical allodynia. Our results suggest that new or currently available drugs targeted at spinal PPAR γ may yield important therapeutic effects for the treatment of neuropathic pain.