Role of central and peripheral tachykinin NK1 receptors in capsaicin-induced pain and hyperalgesia in mice J.M.A. Laird a, * , C. Roza a,1 , C. De Felipe b , S.P. Hunt c , F. Cervero a a Department of Physiology, University of Alcala Â, Alcala  de Henares, E-28871 Madrid, Spain b Neuroscience Institute, Miguel Herna Ândez University, San Juan, E-03550 Alicante, Spain c Department of Anatomy and Developmental Biology, University College London, London WC1E 6BT, UK Received 31 March 2000; received in revised form 28 June 2000; accepted 20 July 2000 Abstract 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 mg capsaicin into the heel evoked paw licking with the same latency in WT and KO mice, but a signi®cantly longer duration in WT mice. A higher dose (30 mg) 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 signi®cant changes from baseline in KO mice. Selective blockade of peripheral NK1 receptors in WT mice resulted in a complete inhibition of capsaicin-evoked plasma extravasa- tion, but the mechanical hyperalgesia induced by 30 mg capsaicin intraplantar was still signi®cantly 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. q 2001 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. Keywords: Substance P; Plasma extravasation; NK1 receptor knockout mice 1. Introduction Intradermal injection of capsaicin, the pungent compo- nent of hot peppers, evokes intense pain and hyperalgesia with negligible tissue damage in both humans and animals (LaMotte et al., 1991; Sakurada et al., 1992; Gilchrist et al., 1996). The duration of the spontaneous pain reaction is dose-dependent, but relatively short. Once the spontaneous pain has abated, a distinctive pattern of hyperalgesia can be observed, with heat and mechanical hyperalgesia close to the site of injection, known as primary hyperalgesia, and a larger area of secondary hyperalgesia in normal skin extend- ing away from the injection site (LaMotte et al., 1991; Gilchrist et al., 1996). The secondary hyperalgesia area is characterized by both punctate and stroking mechanical hyperalgesia, due to changes in the central processing of information from low and high threshold mechanoreceptors, respectively (LaMotte et al., 1992; Cervero et al., 1994). The hyperalgesia is maintained by ongoing activity in noci- ceptors at the site of injection; cooling this site reduces the ongoing activity and the secondary hyperalgesia disappears, but reappears if the injection site is re-warmed (Koltzenburg et al., 1994). The tachykinins substance P and neurokinin A are expressed by primary afferent ®bres and released from the central terminations of these ®bres in the spinal cord by the application of noxious stimuli, including capsaicin injection (Duggan et al., 1988; Mantyh et al., 1995). These peptides have a high af®nity for the NK1 tachykinin receptor (see Quartara and Maggi, 1998), which is expressed on dorsal horn neurones (see Mantyh et al., 1995). Pharmacological Pain 90 (2001) 97±103 0304-3959/01/$20.00 q 2001 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. PII: S0304-3959(00)00394-8 www.elsevier.nl/locate/pain * Corresponding author. Tel.: 134-91-885-4595; fax: 134-91-885-4807. E-mail address: jennifer.laird@uah.es (J.M.A. Laird). 1 Present address: Institute of Physiology and Experimental Pathophy- siology, University of Erlangen-Nu È rnberg, Universita Ètsstrasse 17, D-91054 Erlangen, Germany.