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


Centre for Cardiovascular Biology and Medicine, New Hunt's House, King's College London, Guy's Campus, London SE1 1UL. E-mail:


  • 1Rheumatoid arthritis is a serious, inflammatory disease of the distal joints that has a possible neurogenic component underlying its pathology.
  • 2Substance P (SP), an endogenous neuropeptide that acts upon the neurokinin 1 (NK1) receptor, is released from sensory nerves and is involved in neurogenic inflammation.
  • 3In 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 NK1 knockout mice.
  • 4Detailed analysis in normal mice revealed that CFA (20 μg 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 caused significant acute plasma extravasation, but not other parameters, in wild type (WT), but not NK1 knockout mice. CFA (10 μg induced a significantly decreased intravascular volume, presumably due to decreased blood flow, at early time points (5 and 7 h) in WT but not NK1 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 NK1 knockouts.
  • 5In conclusion, the present study has used novel techniques in WT and NK1 knockout mice to show that SP can modulate vascular tone and permeability in the inflamed joint via activation of the NK1 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