Substance P and its receptor (NK1) are thought to play an important role in
pain and
hyperalgesia. Here we have further examined this role by comparing the behavioural responses to intradermal
capsaicin of mutant mice with a disruption of the NK1 receptor (NK1 KO) and wild-type (WT) mice. We have also evaluated the contribution of peripheral NK1 receptors to
capsaicin-evoked behaviour by selective blockade of peripheral NK1 receptors in WT mice using a non-brain penetrant NK1 receptor antagonist. Injection of 6 microg
capsaicin into the heel evoked paw licking with the same latency in WT and KO mice, but a significantly longer duration in WT mice. A higher dose (30 microg) evoked a similar duration of licking in both groups. There were no differences in mechanical sensitivity tested with von Frey hairs between WT and KO mice before
capsaicin. Both
capsaicin doses resulted in pronounced increases in responses to von Frey hairs (
hyperalgesia) and novel responses to cotton wisps (
allodynia) applied to the digits of the injected paw in WT mice, but no significant changes from baseline in KO mice. Selective blockade of peripheral NK1 receptors in WT mice resulted in a complete inhibition of
capsaicin-evoked plasma extravasation, but the
mechanical hyperalgesia induced by 30 microg
capsaicin intraplantar was still significantly greater than that seen in KO mice. We conclude that the response to intradermal
capsaicin is still present but abbreviated in mice lacking NK1 receptors, such that secondary
hyperalgesia is not observed even after a high dose. Further, the lack of secondary
hyperalgesia in NK1 KO mice is largely due to the loss of central rather than peripheral NK1 receptors. The phenotype of the NK1 KO mice is consistent with a loss of function of mechanically-insensitive nociceptors, and thus we propose that
substance P may be expressed by this group of primary sensory neurones and required for their function.