Molecular biology of TRPV1 and related receptors

Vagal C-fibers form a large majority of the afferent nerves innervating the lungs and airways. These nerves show similar properties to those of the cutaneous C-fibers of somatic sensory populations (dorsal root ganglia neurons) studied in relation to functional and anatomical aspects of nociceptive transmission (1-3). The axons of C-fibers conducting nociceptive signals are unmyelinated and their cell bodies are small in size. Their peripheral terminals are specialized to detect painful (nociceptive) stimuli such as heat, mechanical insults, and inflammatory mediators, and are also referred to as nociceptors (4). Vagal C-fibers initiate bronchoconstriction and some types of cough reflex (5,6), and are closely involved in key aspects of airway diseases associated with hypersensitivity (2,7). The application of nocicep tive stimuli to the airways results in excitation of airway C-fiber afferents leading to the subsequent release of tachykinins and neuropeptides from the fibers, thus causing local effects including smooth muscle contraction (8). Application of capsaicin, a potent activator of a major population of C-fibers, results in cough and neurogenic inflammation (1,9), and induces a functional desensitization of these afferents and depletion of neuropeptides and substance P (SP) in the periphery during disease states (10-12). Finally, large chronic doses of capsaicin reduce airway hypersensitivity to diverse external stimuli (13,14).