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

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.