Capsaicin-sensitive afferents and their role in gastroprotection: an update

Abstract

The pivotal role of capsaicin-sensitive peptidergic sensory fibers in the maintenance of gastric mucosal integrity against injurious interventions was suggested by the authors 20 years ago. Since then substantial evidence has accumulated for the local sensory-efferent function of the released CGRP, tachykinins and NO in this gastroprotective mechanism. This overview outlines some recent achievements which shed light on new aspects and further horizons in this field. (1) Cloning the capsaicin VR-1 receptor (an ion channel-coupled receptor) and raising the VR-1 knockout mice provided a definite molecular background for the existence of capsaicin-sensitive afferents with both sensory and mediator releasing functions in the stomach. This cation channel is also sensitive to hydrogen ions. (2) VR-1 agonists (capsaicin, resiniferatoxin, piperine) protect against gastric ulcer of the rat parallel with their sensory stimulating potencies. (3) Antidromic stimulation of capsaicin-sensitive vagal and somatic afferents results in the release of CGRP, tachykinins, NO and somatostatin. Somatostatin with gastroprotective effect is released from D cells and sensory nerve endings. (4) The recent theory for the existence of spinal afferents without sensory function [P. Holzer, C.A. Maggi, Dissociation of dorsal root ganglion neurons into afferent and efferent-like neurons, Neuroscience 86 (1998) 389–398] is discussed. Data proposed to support this theory are interpreted here on the basis of a dual sensory-efferent function of VR-1 positive afferents, characterized by a frequency optimum of discharges for release vasodilatory neuropeptides below the nociceptive threshold. (5) Recent data on the effect of capsaicin in healthy human stomach are summarized. These results indicate that the gastroprotective effect of capsaicin in the human stomach involves additional mechanisms to those already revealed in the rat.

Introduction

The first evidence for the important role of mediators released from capsaicin-sensitive sensory nerve endings in gastroprotection was published 20 years ago [62]. The theory has been put forward that aggressive factors, e.g. backdiffusion of H⁺ through the mucosa elicit excitation of the capsaicin-sensitive nerve endings, as do mediators released from mast cells (histamine, serotonin and kinins). These sensory stimulants trigger a release of sensory neuropeptides which in turn induce “protective mucosal vasodilatation”. It was already known at that time that capsaicin, the pungent principle in red pepper excites and, after higher doses, impairs the function of a subpopulation of slowly conducting afferents, i.e. the C-polymodal nociceptors in the skin [53], for further Ref. [55]. Thus the protective effect of low concentration of capsaicin (10⁻⁵g/ml) in the Shay ulcer model and aggravation of gastric ulceration in capsaicin desensitized rats to acid distension test and after pylorus ligation were explained by the respective enhancement and blockade of this neural defense mechanism. The role of capsaicin-sensitive afferents in gastroprotection was supported in subsequent series of experiments starting 15 years ago [18], [30], for Ref. see. [2], [25], [32], [43], [45], [52], [69].

During the last 3 years remarkable new achievements were obtained in defining the site of action of capsaicin. Its molecular target, the capsaicin (vanilloid) receptor VR1 has been cloned [12], [24] and VR1 gene-disrupted (VR1 knockout) mice have been generated [10], [13]. In respect of the role of capsaicin-sensitive afferents in gastroprotection the proton-responsive feature of the VR1 receptor ion channel bears particular attention. Therefore the first aim of the present overview is to outline the up-to-date characteristics of the capsaicin-sensitivity, including the proper usage of capsaicin-type agents in gastroprotection. The second part of the article deals with the recently raised theories [26], [27], [32], [56], [57], [66] about the organization of sensory and efferent functions of capsaicin-sensitive nerve endings. The third part of this overview is a brief account of the gastric functions which are influenced by capsaicin-sensitive afferents. In this respect the sensory neuropeptides and nitrergic mechanisms relevant to the gastroprotection are also summarized. The final part of this paper deals with the effects of capsaicin on human gastric functions. This latter aspect formed traditional descriptions of observations with pepper extracts. Nevertheless, owing to the lack of clear physiological or pharmacological experimental design to ascertain the data of animal experiments with those observed in humans a final conclusion about the role of capsaicin in gastroprotection under clinical conditions could not be reached [62].