Mast cell activation or neurogenic inflammation is known to induce lowering of interstitial fluid pressure (P_if) and plasma protein extravasation (PPE) in several tissues from both rats and mice. To examine a possible role of connective tissue mast cells in these inflammatory responses we used mice with dysfunctional mast cells (NDST-2^-/-) lacking a heparinsynthesizing enzyme. P_if and PPE were measured after challenge with C48/80 and PM_if alone was measured following treatment either with capsaicin, substance P (SP) or calcitonin-generelated-peptide (CGRP). Measurements of P_if in anesthetized (Fentanyl/Fluanison, Midazolam, 1:1) mice were performed in paw skin with glass capillaries connected to a servocontrolled counterpressure system. PPE was measured with microdialysis using hollow plasmapheresis fibers (cut-off 3000kDa) placed subcutaneously on the back. Intravenous administration of C48/80 lowered P_if significantly (P < 0.05) in NDST-2^-/- mice (-1.67 ± 0.42 mmHg) compared to vehicle (-0.57 ± 0.17 mmHg) but the lowering was significantly (P < 0.05) less compared to that of the NDST-2^+/+ mice (-2.31 ± 0.47 mmHg). PPE was increased 300 % after treatment with C48/80 in NDST-2^+/+ mice, while there was no increase in PPE in NDST-2-/- mice. Capsaicin, SP and CGRP lowered P_if significantly (P < 0.05) compared to vehicle and to the same extent in both NDST-2^+/+ and NDST-2^-/- mice. We can conclude that although NDST-2^-/- mice demonstrate an altered response in P_if following mast cell activation, there was no similar alteration after neurogenic inflammation. Therefore, we suggest that neurogenic inflammation in mouse skin is not exclusively dependent on intact CTMC's.