Review
Substance P

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Abstract

This article provides a brief overview of the history of substance P from its discovery in the 1930s to the present day. The development of substance P receptor agonists and antagonists, and more recently the employment of transgenic mice, provide a framework to explore the functional role of substance P. Chronic inflammation and pain are associated with a number of diseases, and it has been proposed that substance P, released from primary afferent nerve endings play a role in these conditions. Recent developments with substance P antagonists have demonstrated the importance of substance P in several models of disease that span from asthma to chronic bronchitis; from cystitis, inflammatory bowel disease to migraine; emesis, depression, pain and seizures. Advancements in the knowledge of the role of substance P, its agonists and antagonists could provide clinical solutions for a variety of chronic inflammatory conditions.

Introduction

Substance P was first identified in the early part of the last century, initially isolated as a crude extract from equine brain and gut, and found to have potent hypotensive and smooth muscle contractile properties [1]. Gaddum and Schild [2] named this new agent substance P, P referring to the powder obtained after the extraction procedure. The pioneering work of Lembeck [3] led to the proposal that substance P was a neuronal sensory transmitter associated with pain transmission, due to high concentrations of this agent located in dorsal root of the spinal cord. Further evidence for its role came later with studies by Otsuka and Konishi [4] that showed that substance P immunoreactivity increased in the perfusate taken from isolated spinal cord of newborn rats after application of electrical stimuli. Substance P expression is confined to central nervous system (CNS) and the peripheral nervous system (PNS). Today it is fully recognized that substance P is released from both the central and peripheral endings of primary afferent neurons and functions as a neurotransmitter [5]. The present review focuses on the localization of substance P in the PNS (source being primary sensory nerves and intrinsic neurons of the gut), as much emphasis has been given to the proinflammatory role exerted by substance P released from peripheral endings of primary sensory nerves.

Section snippets

Synthesis and metabolism of substance P

In 1971, Chang et al. [6] identified the amino acid structure of this undecapeptide as H-Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7-Phe8-Gly9-Leu10-Met11-NH2 (Mr 1347.6), in bovine hypothalamus. A decade later it was introduced as part of the tachykinin family [7], along with neurokinin A (NKA) and neurokinin B (NKB) all of which share the same carboxyl terminal sequence, Phe-X-Gly-Leu-Met-NH2 (X is Phe or Val) [5]. Substance P conformation appears to be strongly dependent upon the solvent used and the

Tachykinin receptors

The biological actions of substance P are mediated by tachykinin (neurokinin: NK) receptors, which belong to rhodopsin-like membrane structure, consisting of seven hydrophobic transmembrane domains, connected by extra and intracellular loops and coupled to G-proteins [57], [58], [59]. There are three types of tachykinin receptors, NK1, NK2 and NK3 exhibiting preferences for substance P, neurokinin A and neurokinin B, respectively [10]. However, endogenous tachykinins are not highly selective

NK1 receptor agonists and antagonists

Over the years a large variety of selective agonists have been developed, which have the capacity to activate NK1 receptors at nanomolar ranges (with similar efficacy to that of substance P). It was at the beginning of the 1980s that a series of analogues were designed which included [pGlu6,MePhe8,Sar9]-substance P(5-11) [90], which possessed hypotensive properties in both rat and rabbit [91]. However, it was soon discovered that [pGlu6,MePhe8,Sar9]-substance P(5-11) preferably activated NK3

Neurogenic inflammation

The effects produced by substance P and other tachykinins released from peripheral endings of capsaicin-sensitive primary sensory neurons, are collectively referred to as ‘neurogenic inflammation’ [121] (Fig. 3). Responses produced at the peripheral level by sensory neuropeptides are particularly prominent on the vasculature where they cause vasodilatation of arterioles, plasma protein extravasation in post-capillary venules, and leukocyte adhesion to endothelial cells of venules [121].

Conclusions

After more than 50 years from its discovery substance P is starting to find its place in human physiology and pathophysiology. The emerging role as a neurotransmitter at the level of the central nervous system is gaining attention in depression, nausea, vomiting and pain. On the other hand its well-documented role in the peripheral nervous system as a proinflammatory agent either in the gastrointestinal tract or in other organs represents the rationale for the development of drugs that by

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