Sciatic nerve section in rats evokes chronic limb edema, pain behavior, and hindpaw hyperalgesia, a syndrome resembling the complex regional pain syndrome type II (CRPS II or causalgia) in man. Glucocorticoids such as methylprednisolone (MP) have been used as analgesic and anti-edematous agents in patients suffering from CRPS, and interestingly these therapeutic effects appear to persist in some patients after stopping the medication. Similar to the CRPS clinical response to glucocorticoids, we now demonstrate that chronic hindpaw edema in the sciatic transection CRPS model is reversed by a continuous infusion of MP (3 mg/kg/day over 21 days), and this anti-edematous effect persists for at least 1 week after discontinuing MP. Furthermore, there is a chronic increase in spontaneous protein extravasation in the hindpaw skin of rats after sciatic transection, similar to the increased protein extravasation observed in the edematous hands of CRPS patients. A 2-week infusion of MP (3 mg/kg/day) reduced spontaneous protein extravasation in the hindpaw skin by 80%. We postulated that increased spontaneous neurogenic extravasation resulted in development of limb edema in both the animal model and the CRPS patient, and that the anti-edematous effects of MP are due to an inhibition of spontaneous extravasation. Additional experiments examined the inhibitory effects of MP infusion on electrically-evoked neurogenic extravasation in the hindpaw skin of normal rats. MP inhibition was dose- and time-dependent, with an ED(50) of 1.2 mg/kg/day for a 14-day continuous infusion of MP, and a maximum inhibitory effect requiring 17 days of MP infusion (3 mg/kg/day). MP (3 mg/kg/day for 14 days) also blocked both capsaicin- and SP-evoked neurogenic extravasation, indicating a post-junctional inhibitory effect. Our interpretation is that increased spontaneous neurogenic extravasation in this CRPS model contributed to the development and maintenance of hindpaw edema, and that chronic MP administration dose- and time-dependently blocked neurogenic extravasation at a post-junctional level, thus reversing spontaneous extravasation and limb edema in this model.