Role of central and peripheral tachykinin NK1 receptors in capsaicin-induced pain and hyperalgesia in mice

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 comparin g the behavioural responses to intradermal capsaicin of mutant mice with a disruption of the NK1 receptor (NK1 KO) and wildtype (WT) mice. We have als o evaluated the contribution of peripheral NK1 receptors to capsaicin-evoke d behaviour by selective blockade of peripheral NK1 receptors in WT mice us ing a non-brain penetrant NK1 receptor antagonist. Injection of 6 mug capsa icin into the heel evoked paw licking with the same latency in WT and KO mi ce, but a significantly longer duration in WT mice. A higher dose (30 mug) evoked a similar duration of licking in both groups. There were no differen ces in mechanical sensitivity tested with von Frey hairs between WT and KO mice before capsaicin. Both capsaicin doses resulted in pronounced increase s in responses to von Frey hairs (hyperalgesia) and novel responses to cott on 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 ca psaicin-evoked plasma extravasation, but the mechanical hyperalgesia induce d by 30 mug capsaicin intraplantar was still significantly greater than tha t seen in KO mice. We conclude that the response to intradermal capsaicin i s still present but abbreviated in mice lacking NK1 receptors, such that se condary hyperalgesia is not observed even after a high dose. Further, the l ack 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 m ice is consistent with a loss of function of mechanically-insensitive nocic eptors, and thus we propose that substance P may be expressed by this group of primary sensory neurones and required for their function. (C) 2001 Inte rnational Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.