The present study was undertaken to determine whether propentofylline, a glial modulating agent, could both prevent the induction of mechanical allodynia and attenuate existing mechanical allodynia in a rodent L5 spinal nerve transection model of neuropathic pain. In a preventative paradigm, propentofylline (1 and 10 mg/kg intraperitoneally) was administered systemically daily, beginning 1 day prior to nerve transection. This regimen produced a dose-dependent decrease in mechanical allodynia (p < 0.01). In another preventative paradigm, propentofylline (0.1, 1, or 10 microg) was administered daily intrathecally via direct lumbar puncture. Intrathecal administration of propentofylline was more effective than systemic administration at dose dependently reducing mechanical allodynia (p < 0.01). The effect of systemic propentofylline on existing allodynia was examined with 0.1-, 1-, and 10-mg/kg intraperitoneal administration initiated on day 4 post L5 spinal nerve transection. Systemic propentofylline was found to be equally effective in the attenuation of existing allodynia (p < 0.01) as in the prevention of allodynia in this rodent model of neuropathic pain. Spinal cords (L4-L6 segments) were removed for immunohistochemical analysis on day 10 or 20 post-transection. Microglial and astrocytic activation was decreased by both peripheral and central administration of propentofylline in both preventative and existing allodynia paradigms. This research supports a growing body of literature highlighting the importance of glial activation in the development of persistent neuropathic pain states, and the potential to therapeutically modulate glial activation in the treatment of neuropathic pain.