The role of substance P in microvascular responses in murine joint inflammation

Abstract

Rheumatoid arthritis is a serious, inflammatory disease of the distal joints that has a possible neurogenic component underlying its pathology. Substance P (SP), an endogenous neuropeptide that acts upon the neurokinin 1 (NK 1) receptor, is released from sensory nerves and is involved in neurogenic inflammation. In this study, we have developed novel techniques to determine the contribution of SP to microvascular responses in a model of complete Freund's adjuvant (CFA)-induced arthritis in NK 1 knockout mice. Detailed analysis in normal mice revealed that CFA (20 μg i.art.)-induced plasma extravasation was raised from 18 to 72 h, when compared with intravascular volume. By comparison, knee swelling was sustained for 3 weeks. Neutrophil accumulation mirrored plasma extravasation. SP (10pmol i.art.) caused significant acute plasma extravasation, but not other parameters, in wild type (WT), but not NK 1 knockout mice. CFA (10 μg i.art.) induced a significantly decreased intravascular volume, presumably due to decreased blood flow, at early time points (5 and 7h) in WT but not NK 1 knockouts. Otherwise, similar responses in WT and NK1 knockout mice were observed. However, injection of SP into CFA-pretreated joints caused a significant enhancement of plasma extravasation and knee swelling in the WT but not NK 1 knockouts. In conclusion, the present study has used novel techniques in WT and NK 1 knockout mice to show that SP can modulate vascular tone and permeability in the inflamed joint via activation of the NK 1 receptor and that SP-induced responses are more pronounced where pre-existing inflammation is present. © 2005 Nature Publishing Group All rights reserved.