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

1 Rheumatoid arthritis is a serious, inflammatory disease of the distal joints that has a possible neurogenic component underlying its pathology. 2 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. 3 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. 4 Detailed analysis in normal mice revealed that CFA (20  μ g 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 (10 pmol i.art.) caused significant acute plasma extravasation, but not other parameters, in wild type (WT), but not NK 1 knockout mice. CFA (10  μ g i.art.) induced a significantly decreased intravascular volume, presumably due to decreased blood flow, at early time points (5 and 7 h) in WT but not NK 1 knockouts. Otherwise, similar responses in WT and NK 1 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. 5 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.British Journal of Pharmacology (2005) 144 , 1059–1066. doi: 10.1038/sj.bjp.0706131