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VANILLOIDS: HOT RELIEF FOR PAIN Pace of research on pain treatment with vanilloids heats up on several fronts A. Maureen Rouhi C&EN Washington
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anilloids. The word brings to mind vanilla, sweets. The compounds collectively called "vanilloids" are anything but sweet, however. At best, they1 re hot, spicy. At worst, they're infernal irritants. The quintessential vanilloids are capsaicin and resiniferatoxin (RTX). Capsaicin is the pungent compound in red peppers. It is an ingredient of some overthe-counter pain-relieving creams and is the basis of personal-defense sprays as well as squirrel-proof birdseed (C&EN, March 4, 1996, page 30). RTX is a potent irritant from Euphorbia resinifera. The latex of this cactuslike plant is well known for its medicinal effects. According to a review by Arpad Szallasi, a pharmacologist at Washington University Medical School, St. Louis, and Giovanni Appendino, a chemist at Università degli Studi di Torino, Torino, Italy [Life Sci., 60, 681 (1997)], the latex is described in medical literature dating back to the first century as a nose- and skin-irritating agent as well as a treat-
ment for chronic pain. The powdered latex also was used for practical jokes: inducing general sneezing of the high society gathered for a ball, for example. Both capsaicin and RTX contain the homovanillyl group in their structures, hence the collective term. And when applied to the skin or mouth, they cause a burning sensation by binding to receptors in small sensory neurons associated with transmitting pain—so-called C sensory nerve fibers (C&EN, Dec. 15, 1997, page 48). But the initial irritation, even pain, is temporary. Repeated applications cause desensitization, an effect that can be used to treat pain. Rapid progress is being made in the area of therapeutic vanilloids, including the discovery of compounds that are recognized by vanilloid receptors but do not have the homovanillyl moiety; the cloning of the gene for a vanilloid receptor; and the first total synthesis of RTX. These achievements should provide even more tools for further understanding pain at the molecular level and for the design of new painkillers. It's nice and neat to regard vanilloids as a family with a structural common denom-
inator and a singular human-perceptible effect, such as spiciness. After all, other vanilloids are very similar to the archetypal capsaicin. For example, zingerone, a compound from ginger, has the homovanillyl group, and ginger is, well, spicy. RTX and the plant it comes from, however, have no known culinary use, perhaps because the compound is too fiery even for the most avid lovers of spicy food. The orderly structure-activity picture is becoming complicated with the finding that compounds that do not look like or feel like capsaicin or RTX can interact at vanilloid receptors. For example, Szallasi has found that some hot-tasting terpenoids have vanilloid-like activity. Examples are polygodial, found in water peppers used in Chinese and Japanese cuisine, and isovelleral, found in a pungent edible mushroom. Neither polygodial nor isovelleral contain the homovanillyl moiety. Even more intriguing is the phenolic terpenoid called scutigeral. Not only does it not contain the homovanillyl group but it also tastes benign. Scutigeral shows that a ligand does not have to be an irritant to interact with the vanilloid receptor. In theory," says Szallasi, "compounds like scutigeral may act as orally active, nonpainful painkillers targeting vanilloid receptors." What ultimately unifies these compounds is the ability to bind to the same receptors, which researchers will continue to call vanilloid receptors for lack of a better term. In 1968, the Hungarian pharmacologist Nicholas Jancso first predicted the existence of vanilloid receptors, specifi-
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JANUARY 26, 1998 C&EN 31
science/technology cally for capsaicin. It wasn't until 1990 that pharmacologist Peter M. Blumberg and Szallasi, both then at the National Cancer Institute, Bethesda, Md., found direct evidence for such receptors. Last October, pharmacologist David Julius and coworkers at the University of California, San Francisco, cloned the gene for the capsaicin receptor [Nature, 389, 816 (1997)1. Large quantities of this receptor now can be produced easily for use in research to test potential analgesics and to help guide the development of new drugs. On the basis of the well-known ability of capsaicin to activate calcium ion channels, Julius and coworkers used a calcium-imaging technique to track the gene. They isolated messenger RNA from neuronal cells and constructed a gene library, which the}7 divided into several pools. Each pool was introduced into nonneuronal cells, which were then loaded with a fluorescent calcium-sensitive dye. In cells that express the receptor, calcium levels change in the presence of capsaicin, causing the dye to fluoresce differently. "We used that change in fluorescence to look for this receptor," says Julius. After several iterations of the process, the researchers obtained a single 3-kilobase complementary DNA that codes for the receptor. The receptor responds not only to capsaicin but also to tissue-damaging levels of heat, the study shows. "We believe hot peppers feel hot because capsaicin
receptor but a family of receptors exists. Blumberg and Szallasi have established the existence of receptors that are selective for capsaicin (C type) and those selective for RTX (R type). The receptor cloned by Julius and coworkers is the first example of a C-type receptor, says Blumberg. "So there's some more fun still to go in the cloning." Blumberg and Szallasi believe different receptors are coupled to different biological responses. For example, although both capsaicin and RTX have pain-inducing and desensitizing effects, the balance of those effects is different for the two compounds. These differences are reflected in recent therapeutic applications. Capsaicin had been a candidate drug for the treatment of bladder hyA physician (right) oversees collection perreflexia, which is a condiof Euphorbium latex by an attendant, as shown tion characterized by the feelin a manuscript dated 1244. ing that one needs to empty the and heat stimulate the same protein sen- bladder even when it contains only a small amount of urine. The condition is sor in the neurons," says Julius. But there must be more to this recep- controlled by a spinal reflex triggered by tor than just detecting hot peppers and C sensory nerve fibers, which are excitheat, because Szallasi says it is found ed (and thus cause pain) and then deseneven in the brain and in the bladder. For sitized by capsaicin. Although capsaicin this reason, both Szallasi and Blumberg effectively relieves the condition, the believe the receptor must have still- first application causes an intense burning sensation that patients cant tolerate, undiscovered endogenous activators. To further complicate the picture, ear- says Szallasi. On the other hand, C sensory nerve lier studies have shown that not just one
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