Substance-P-induced protein extravasation is bilaterally increased in complex regional pain syndrome

Pain, mechanical hyperalgesia, edema, increased skin temperature, and skin reddening are characteristic symptoms of acute complex regional pain syndrome (CRPS). We have recently demonstrated facilitated neurogenic inflammation on the affected limb. To further elucidate the underlying mechanisms, exogenous substance P (SP) in ascending concentrations (10(-9), 10(-8), 10(-7), 10(-6) M) was intradermally applied to the affected and the unaffected limbs, respectively, in two groups of 11 CRPS patients each using the microdialysis technique. Fourteen healthy volunteers served as controls for SP application, and 9 volunteers and 10 patients served as controls for saline perfusion. Dialysate protein content was measured photometrically to assess plasma protein extravasation. Significant differences in dialysate protein content were found after 10(-9) M SP (affected side, 98.4 +/- 8.4% of baseline value; unaffected side, 104.4 +/- 5.6%; controls, 70.7 +/- 4.1%; P < 0.005) and after 10(-6) M SP (affected, 169.7 +/- 24.2%; unaffected, 189.4 +/- 19.1%; controls, 122.2 +/- 12.0%; P < 0.05). While 10(-9) M SP induced no protein extravasation in controls, it provoked protein extravasation in 6 of 11 patients on the affected and in 5 of 11 patients on the unaffected side (P < 0.01). We conclude that SP-induced plasma protein extravasation is increased in CRPS patients on both the affected and unaffected limbs. The underlying mechanism might be impaired SP inactivation. Thus, our results further support the hypothesis that neurogenic inflammation plays an important role in the initiation of CRPS.