In recent years remarkable breakthroughs have opened up for drug research by the identification of new cellular target molecules with validated pathobiological significance. Most of these target identifications were made with the aid of wonderful exogenous lead molecules often made by nature in different plants or animal poisons. Capsaicin is certainly one of these promising lead molecules. Its powerful, selective pain producing and desensitizing effects were first described by Andreas Hogyes (1878) and Nicholas Jancso (I960), respectively. Subsequently, postulation of a new receptor molecule the "capsaicin receptor" in cell membrane of a subgroup of primary afferent neurons was proposed (Szolcsanyi and Jancso Gabor, 1975, 1976). This hypothesis was put forward on the basis of four sets of observations made by our group in the late sixties and early seventies (Szolcsanyi, 1982, 1984a; Buck and Burks, 1986; Holzer, 1991; Maggi, 1995).
1 The potent pungent effect of capsaicin turned out to be absent in several species. Nociceptive protective reflexes were not evoked in non-mammalian species such as frog, chicken or pigeon.
2 The loss of sensation evoked by high concentration of capsaicin is highly selective, as revealed by quantitative psychophysical assessments on the human tongue after topical capsaicin application. Hot or irritant pain sensation induced by capsaicin, piperine, zingerone or mustard oil was not detectable. Noxious heat threshold was enhanced and warmth discrimination was impaired after capsaicin treatment. On the other hand, taste stimuli, difference limen in the cold range, threshold concentration of menthol and tactile sensation remained unchanged.
3 Structure-activity relationship showed that small changes in the capsaicin structure have profound effect on its agonist activity. Furthermore, pharmacophores required for the excitatory and sensory blocking effects of the capsaicin congeners were partially different.
4 The capsaicin-sensitive subgroup of primary afferent neurons was identified by the ultrastructural changes induced by systemic treatment of rats with high doses of capsaicin. Capsaicin-responsive cells were the small, dark, B-type neurons of the trigeminal, nodosal and dorsal root ganglia, as well as a subgroup of small neurons in the hypothalamic medial preoptic area, where the central warmth sensors are situated in high density. Light, A-type primary afferent neurons and satellite cells in these ganglia, or cellular elements of the sympathetic ganglia were not altered.
Subsequently, the neuroselective site of action of capsaicin was supported in our further electrophysiological and in vitro pharmacological studies. Close arterial injections of capsaicin in rabbit, rat and cat selectively activated cutaneous C- and A-delta polymodal nociceptors which comprise about 50% of the population of the primary afferent neurons. On the other hand, all types of mechanoreceptors, including the A-delta mechanonociceptors or C-mechanoreceptors, were not activated by capsaicin (Szolcsanyi, 1993, 1996). Furthermore, neuroeffectors which mediate cholinergic, adrenergic, purinergic, peptidergic autonomic and intrinsic enteric neurotransmissions in the guinea-pig gut were not influenced by capsaicin (Maggi, 1995).
With the advent of the neuropeptide era, capsaicin gained considerable interest outside Hungary when in 1978 Tom Jessell, Leslie Iversen and Cuomo Cuello, and soon after Fred Lembeck's group in Graz and Masanori Otsuka's group in Japan, clearly showed that capsaicin releases and subsequently depletes substance P from the primary afferent neurons and their terminals but not from other parts of the nervous system (Holzer, 1991; Maggi, 1995). Capsaicin in this way turned out to be the first drug which selectively depleted a neuropeptide from a population of neurons.
Afterwards, various ways of systemic or local pretreatments with capsaicin were utilized in a broad scale to reveal the presence and role of substance P, somatostatin and the newly identified neuropeptides e.g. CGRP, VIP, bombesin, etc. in sensory neurons and in their peripheral or central axonal arborizations. Most of these data were obtained in rats pretreated with capsaicin in the neonatal age since it had been suggested that this treatment induce an acute selective cell death of the chemosensory afferent population (Jancso et al., 1977). Re-evaluation of these early data was needed, however, subsequent studies revealed a lack of selectivity in the loss of C-polymodal nociceptors in these animals (Welk et al., 1984; Szolcsanyi, 1990; Nagy et al., 1983) which might be related to long-term phenotype changes and reorganization of the pathways. Furthermore, it was recently reported that the loss of C-afferents observed in the adult age develop after a week and not within 30 minutes as it was initally emphasized (Szolcsanyi et al., 1998b). The data obtained in animals pretreated in the adult age indicated a selective inactiva-tion and loss of noxious heat responsive afferents, the major group of which is the C-polymodal nociceptors (Szolcsanyi, 1990, 1993). Subsequently the capsaicin receptor was cloned (Caterina et al., 1997) and the molecular biological repertoire for high throughput screening has opened the means for the discovery of the first putative analgesic acting at the level of nociceptors. The aim of the present overview is to focus on the perspectives of this drug research from a standpoint of describing the present state of knowledge in this field. Furthermore, new trends in peptidergic neuroregulatory mechanisms, which suggest that this capsaicin-sensitive substantial portion of the sensory neurons subserve local efferent and systemic "sensocrine" functions (Szolcsanyi, 1996; Than et al., 2000) are discussed briefly in this chapter.
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