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Apart from pungency, the first pharmacological property discovered for capsaicin was the capacity to induce hypothermia (Szallasi and Blumberg, 1999). Capsaicin can induce a profuse perspiration, so-called gustatory sweating, which leads to a decrease of body temperature and is probably responsible for the popularity of hot pepper in warm climates, where heat loss is beneficial. Capsaicin is a pleiotropic pharmacological agent that shows activity in an impressive variety of pharmacological assays. However, some of these activities, like neurotoxicity, can be evidenced only at high doses, and are probably aspecific and of no dietary or practical pharmacological relevance. Nowadays, research on capsaicin focuses mainly on its analgesic and appetite-suppressant activities. Capsaicin is the archetypal vanilloid, a class of compound which targets a heat-sensitive ion channel (the so-called vanilloid receptor-1, VR1) involved in pain sensation and neurogenic inflammation (Szallasi and Blumberg, 1999). Under physiological conditions, the channel is activated by an increase of temperature and a fall in pH. Binding of capsaicin lowers the temperature threshold of the channel, which is activated at room temperature also by what would otherwise be subliminal stimuli (Caterina et al., 1997). Expression of VR1 is not limited to the nerve endings of the lingual epithelium, but is typical of a set of neurons involved in pain sensation and neurogenic inflammation.

Binding to VR1 underlies the biological activities of capsaicin. This compound acts as a sort of 'heat surrogate', and ultimately causes desensitization of the receptor, with block of transmission of algic information (Caterina et al., 1997). The endocannabi-noid anandamide shows vanilloid activity, and has been suggested as the endogenous modulator of VR1 (Szolcsanyi, 2000). Both the murine and the human versions of the receptor have been cloned, and knock-out mice for VR1 have also been generated (Caterina et al., 2000). These animals have an impaired pain sensation, but are otherwise normal, an observation which validates VR1 as a pharmacological target. The sheer frequency at which hot pepper has been featured on the front cover of the major scientific journals testifies the current excitement on vanilloid research.

Data on the oral bioavailability of capsaicin are contradictory, and this compound is partly eliminated with the faeces, causing intense anal burning. For these reasons, capsaicin is employed only in topic forms, as a constituent of pain-relieving preparations. The initial strong burning sensation causes problems with patients' compliance, greatly limiting the use of these products, whose efficacy is obviously difficult to assess in double-bind studies. Furthermore, capsaicin is poorly absorbed from the human skin, where it is extensively metabolized by amidases (Szallasi and Blumberg, 1999).

Despite these limitations, the manipulation of the vanilloid receptor has great relevance to the discovery of new analgesics, and capsaicin has indeed been at the centre of three major industrial medicinal chemistry efforts (Procter & Gamble, Sandoz, Glaxo) (Wrigglesworth and Walpole, 1998). These investigations failed to substantially improve the natural product, but detailed the structure—activity relationships, and led to the discovery of the non-pungent analogue olvanil and the vanilloid antagonist cap-sazepine. Orally active analogues have been synthesized, and one of them, capsavanil, is currently undergoing pharmaceutical development in the USA and Korea (Park et

Various explanations have been put forward as to why humans crave culinary pungency. In this context an interesting observation is that the bark of Warburgia uganden-sis, which is used in Africa just like hot pepper, contains the pungent dialdehyde warburganal (14a), while another pungent dialdehyde, polygodial (14b) is contained in the European water pepper (Polygonum hydropiper L.), once used as a pepper substitute (Sterner and Szallasi, 1999). These unsaturated dialdehydes behave as biological analogues of capsaicin, targeting VR1 and evoking responses not unlike those elicited by capsaicin. Also piperine (15) from black pepper (Piper nigrum L.) shows vanilloid activity, suggesting a remarkable molecular convergence of pungency target between the hot cuisine of America, Africa, Europe and Asia. Capsaicin has gastroprotective activity, and chilli pepper has been shown to counteract the adverse gastric effects of aspirin and to display bactericidal activity against Helicobacter pylori (Szallasi and Blumberg, 1999). The beneficial effects of pungent compounds on the gastrointestinal tract, along with their effects on body temperature, have undoubtedly contributed to the popularity of hot cuisine.

Dietary hot pepper increases energy expenditure and diminishes long-term excess energy intake, making capsaicin a potential slimming agent (Henry and Emery, 1986). This activity might be related to the presence of vanilloid receptors in the area postrema and the nucleus of the solitary tract, a zone involved in satiety (Szallasi and Blumberg, 1999). Though relatively unexplored, this area might receive increasing attention on account of the current social relevance of obesity.

Last but not least, capsaicin is also interesting for cancer research, curiously both as an anticancer and as a cancer-inducing agent. Capsaicin selectively inhibits plasma membrane NADH oxidase of cancer cells, binding to an enzyme (tNOX) which is expressed specifically on tumour cells (Morre et al., 1995). Claims that hot pepper al, 2000).

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