In response to tissue injury or infection a complex series of homeostatic reactions involving the immune, circulatory and nervous systems occur, a response that is termed inflammation. In cutaneous tissues, the processes of inflammation lead to four well described clinical signs; heat, redness, edema and pain. I These are caused by vasodilatation, plasma extravasation and sensitization and activation of nociceptive C-fiber nerve endings.* The concept of neurogenic inflammation arose in the early twentieth century, based on the observation that antidromic stimulation of sensory nerves produced a cutaneous vasodilatation associated with an increase in vascular permeability, leading to extravasation of plasma protein^.^^^ In many investigations the sensory neurotoxin, capsaicin was used to show that a population of small diameter, chemosensitive, primary afferent nerve fibers gave rise to neurogenic inflammation (reviewed in refs. 4-6), culminating in Lembeck’s proposal that the undecapeptide, substance P was the chemical mediator of this response. 233

Substance P is a member of a family of peptides called the tachykinins.’In mammals, this family consists of substance P, neurokinin A (NKA), neurokinin B (NKB) and two N-terminally extended forms of NKA, neuropeptide K and neuropeptide y. The precursors of the tachykinins are generated by two distinct genes, preprotachykinin (PPT) A and B. PPT-A can be alternatively spliced to encode for substance P alone, or substance P and the NKA products. The PPT-B gene encodes only NKB (reviewed in refs. 7-9).* The hypothesis that substance P was the mediator of neurogenic inflammation was strengthened when it was shown that substance P caused vasodilatation and plasma extravasation and that this could be abolished by substance P antagonists and antibodies to substance P. Io-l4 Moreover, the effect of antidromic stimulation was also abolished by these agents and, in addition, by capsaicin The site of action of substance