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Tibia fracture in rats evokes chronic hindpaw warmth, spontaneous extravasation, edema, allodynia, and periarticular bone loss, a syndrome resembling complex regional pain syndrome type I (CRPS I). Glucocorticoids such as methylprednisolone (MP) are probably effective analgesic and anti-edematous agents in patients suffering from CRPS and this study examined the effects of chronic MP treatment in the rat CRPS I model. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and the hindlimb bone density was measured using dual-energy X-ray absorptiometry (DXA). Spontaneous cutaneous extravasation and substance P infusion evoked extravasation were determined using an Evans blue vascular permeability assay. After baseline testing, the distal tibia was fractured and the hindlimb casted for 4 weeks. At 2 weeks post-fracture MP infusion was started (1 mg/kg/day for 28 days). The rats were retested at 4, 6, and 8 weeks post-fracture. Hindpaw edema and warmth after fracture were reversed by MP infusion and these effects persisted after discontinuing treatment. Furthermore, there was an increase in spontaneous protein extravasation and an enhanced substance P evoked extravasation and edema response in the hindpaw at 4 weeks that was inhibited by MP infusion. Glucocorticoid treatment had no effect on the allodynia, hindpaw unweighting, or the periarticular bone loss observed after tibia fracture. We postulate that post-junctional facilitation of substance P signaling contributes to the hindpaw warmth, edema, and the enhanced spontaneous protein extravasation observed in this CRPS I model, and that the anti-edematous effects of glucocorticoid treatment are due to inhibition of post-junctional neuropeptide signaling.