From the time of its origination, New World Indians might have been cultivating capsaicin over 5000 years ago (Weil 1981). The Incas used liquid capsicum and the smoke of burning pods as agents of chemical warfare (Weil 1981). Also, it was customary for the Mayans to rub chili into the eyes of young girls caught glancing at men. Native Americans used Capsicum as a medicine to cure cramps as well as diarrhea. By the middle of the 1600s, the cultivation of Capsicum spread throughout the world. Even nowadays capsaicin is a standard ingredient in over-the-counter drugs used to relieve muscle pain. Capsaicin is also used as a therapeutic for appetite stimulation, treatment of gastric ulcers and rheumatism. Besides its use for food additives and potential drug as a pain killer agent, capsaicin is also the ingredient for martial purposes. At present, capsaicin spray is used for "aerosol restraint" by over two thousand local law enforcement agencies in the US, and is marketed in California for personal defense. It was not until 1878 that an experiment with the active ingredient in hot pepper was observed to act on nerve fibers.
The precise mechanism of action remained evasive yet through electrophysiological and biochemical studies a possible action is revealed. Spicy foods excite the nerve endings in the skin, lining of the mouth and digestive tract that normally respond to high temperature or injury. Capsaicin produces burning pain as it initially excites polymodal nociceptors by interacting with a specific receptor, which eventually opens cation channels (Simone et al. 1998). Following this action the inactivation of voltage-gated ion channels prevents generation of action potentials which may account for the short-lasting desensitizations and the burning pain. It has been shown that capsaicin releases substance P and calcitonin gene-related peptide from the peripheral endings of primary afferent fibers that are responsible for pain pathways (Simone et al. 1998). The nociceptors are found in the skin and mucous membranes (lining of the mouth and digestive tract). The receptors are described as polymodal because they are sensitive to noxious heat, mechanical, and chemical stimuli (WWW1). These neurons transmit information regarding tissue damage to pain-process centers in the Central Nervous System (CNS). The brain makes a judgement based on the type of stimuli being received and occasionally misinterprets the information. Therefore, the stimulation produced by the chemicals in the spicy food causes the brain to perceive an extreme of heat and initiate responses such as sweating and vasodilations (WWW3). The reason people have failed to achieve comfort by drinking cold water to relieve the burning sensation from spicy foods is primarily because it is insoluble in water.
Since capsaicin's molecular mechanism in the nervous system is unclear, researchers observe a functional screening assay to isolate a cDNA clone that reconstitutes capsaicin responsiveness. From the sequence of this clone it shows that the capsaicin receptor is a protein. It seems that capsaicin action is very selective, noted from observing how the cloned receptor was expressed exclusively by small-diameter neurons within sensory ganglia (Caterina et al. 1997). The molecular receptor named vanilloid receptor type 1 (VR1), is embedded in the cell membrane which respond to capsaicin, high temperature and local tissue damage. Vanilloid is a group that chemically characterizes capsaicin. In sensory neurons, vanilloid-evoked currents are carried by both monovalent and divalent cations. To examine the relative contributions of various cations to capsaicin-evoked currents several ion substitutions experiments is done in VR-1 expressing cells (Caterina et al. 1997). The cells bathed in different cationic solutions show how VR1 exhibits a notable preference for divalent cations. There is a high permeability of VR1 to calcium ions. This leads to the reasoning of why physiological desensitization produced by vanilloids seems to depend, partly by the presence of calcium. Capsaicin activates the VR1 and causes calcium ions to flow into the nerve ending that initiates nerve impulses that pass to the brain where they are interpreted as a burning pain. Also, the behavior of VR1 response is examined. During the experiment currents of unitary amplitude were noticed, which indicates that capsaicin-gated ion channels do exist.
Through understanding the detailed mechanism supported by the experiments, it is plausible to see how capsaicin excites and subsequently desensitizes a group of small sensory neurons which makes it a useful tool to apply it to the skin to relieve a variety of painful syndromes. With prolonged exposure, nociceptor terminals become insensitive to capsaicin as well as to other noxious stimuli (Caterina et al. 1997). It has been demonstrated experimentally that after ingesting capsaicin or even the application of it directly on the skin, the severity of pain is directly proportional to the concentration of capsaicin present. After a single exposure, burning pain occurs quickly but wanes gradually. If capsaicin exposure is repeated promptly, before the burning sensation from a previous exposure has dissipated, sensitization may occur (WWW1). On the other hand, if capsaicin exposure is repeated after the burning sensation from a previous exposure has dissipated, nociceptor desensitization occurs (WWW1). This is due to the fact that capsaicin elevated the threshold for pain in the specific area that it is exposed. Therefore, the pain threshold can be further elevated by gradually increasing the capsaicin concentration with repeated applications.
When capsaicin is applied to inflamed oral mucosa, the mucositis pain diminishes as the burning sensation caused by capsaicin subsides. Theoretically, when concentration of capsaicin is increased in order to produce burning pain approximately equal to a patient's level of pain due to mucositis pain, the mucositis pain may diminish or disappear as the sensation from capsaicin dissipates (WWW1). Continuous exposure to capsaicin which causes the decreased sensitivity to noxious stimuli may result from reversible changes in the nociceptor, but the long-term desensitization can be explained by how capsaicin destroys a subset of small diameter primary afferent fibers and their cell bodies (Simone et al. 1998).
A study demonstrates that intradermal injection of capsaicin produces degeneration of nerve fibers in the epidermis as well as superficial dermis. This is shown from the study with the degeneration of immunoreactivity for protein gene product (PGP) 9.5. Yet amazingly, although PGP 9.5 degenerates it subsequently regenerates (Simone et al. 1998). The first observation shows that capsaicin is the only the site of injection and only to those nerve fibers that came in contact with capsaicin became affected. Although capsaicin seems to produce a gradual degeneration of fibers from the nerve endings in the epidermis this pattern of dying back is common with various types of clinical neuropathies, such as diabetic neuropathy and neuropathy associated with human immunodeficiency virus injection (Simone 1998). A reinnervation is observed even though there is repeated application of capsaicin. Those fibers in the epidermis regain the ability to be sensitive to heat and sharp pain. Therefore, although intradermal injection may be unsafe to a certain extent, capsaicin as an ointment application has a slower onset and is not as severe.
Epidemiologist studies reveal that diet plays a major role in the prevention of various types of human cancer. Approximately 350f all cancer deaths are attributable to dietary factors (Surh et al. 1997). Numerous phytochemicals are sought after and studies, particularly those included in our diet. It has been found that many phenolic substances in our diet show chemopreventive effects against it has been found that many phenolic substances in our diet show chemopreventive effects against experimental carcinogenesis and mutagensis (Surh et al. 1997). Capsaicin as well as other spices contains bioactive phenolic substances that have potent antioxidants with chemopreventive properties.
A study is done to investigate capsaicin's chemoprotective properties against carcinogens and mutagens. Experiments with rats demonstrate that it affects the initiating activities of certain chemical carcinogens such as benzo [a]pyrene through modulation of their metabolism. Benzo[a]pyrene-induced pulmonary tumors in mice were inhibited by capsaicin treatment (Surh et al. 1997). Not only did it inhibit the tumor growth, but capsaicin also displays inhibitory effects on metabolism and covalent DNA binding of aflatoxin (Surh et al. 1997). Also, capsaicin exhibits an inhibitory effect on hamster microsome-mediated mutagenicity of the tobacco-specific nitrosamine and lowers the mutagenicity of urban air samples (Surh et al. 1997). Capsaicin pretreatment also protects against the free radical pulmonary damage in rats that have been exposed to gaseous chemical irritants such as sulfur dioxide and nitrogen dioxide.
Moreover, hot peppers have high vitamin C, which, in turn, may be effective in protecting against cancer (WWW4). As already known, vitamin C is an antioxidant, a chemical substance capable of removing free radicals, which can cause cells to mutate. Just by weight, green bell peppers, not containing capsaicin, have twice as much vitamin C as citrus fruit. Red peppers have three times as much. Even still, hot peppers contain more vitamin C. It contains 357 percent more vitamin C than an orange (WWW4).
Although initial application of capsaicin causes minor irritation and complications, reapplication of this substance suppresses the inflammatory response as seen in rats. Substance P has been suggested as a proinflammatory mediator in ultraviolet irradiation-induced cutaneous inflammations in rats and is also a promoter of gastric carcinogenesis (Surh et al. 1997). Capsaicin's interference with substance P as it depletes substance P from local sensory nerve terminals, and thereafter suppresses the substance-mediated flare response in human skin demonstrates its usefulness. The observed anti-inflammatory effects of capsaicin appear to be related to its interference with phospholipase A that plays a crucial role in inflammation (Surh et al. 1997). Therefore, capsaicin, when treated to macrophages, repressed calcium-ionophore stimulated pro-inflammatory responses, such as generation of superoxide anion, phospholipase A2 activity and membrane lipid peroxidation (Surh et al. 1997). Since tumor development correlates to inflammatory processes which can stimulate the growth of initiated cells, it makes plausible sense that capsaicin should work as an anti-tumor promoting agent. A study shows that application of capsaicin prevents epithelial thickening and appearance of atypical cells. Many studies have demonstrated the anti-inflammatory activity of capsaicin. Direct injection of capsaicin into a mouse melanoma significantly suppressed the growth of tumors.
A detailed study of the chemoprotective effect of capsaicin against mutagensis or tumorigenensis is done. Sprague-Dawley rats treated with vinyl carbamate (VC) and N-nitrosodimethlamine (NDMA) supports the hypothesis of the chemopreventive effects. Capsaicin interacts with microsomal xenoiotic metabolizing enzymes in the study done. It mechanistically binds to the active sites of the enzyme and the inhibition by capsaicin of microsomal monoxygenases involved in carcinogen activation implies its chemopreventive action. This study reveals that capsaicin protects against VC and NDMA, which are converted to mutagenic tumorigenic metabolites (Surh et al. 1995). Topical application of capsaicin prior to VC showed significant inhibition of initiation of mouse skin tumors by the carcinogen.
Along with the chemopreventive measure of capsaicin, it also helps protect gastric mucosal injury from alcohol. Capsaicin injected intragastrically protects the gastric mucosa against macroscopic damage produced by alcohol concentrations ranging from 25-100% (Kang 1995). With the use of scanning electron microscopic it is confirmed that there is a gastroprotective effect of intragastric capsaicin. Dietary supplementation with chili for four weeks was associated with a reduction in ethanol induced gastric mucosal damage (Kang 1995). Capsaicin also increased the secretion of mucus into gastric juice. The pathophysiological reasoning of gastroprotection by capsaicin is unclear. It has been reasoned that increase in gastric mucosal blood flow due to capsaicin may be related to the release of calcitonin gene related peptide with the participation of nitric oxide (Kang et al. 1995). Even with a single dose of capsaicin given subcutaneously the results are similar. Also, chili powder in amounts similar to those consumed by humans they are confirming results that shows the gastroprotective effect of capsaicin is reproducible by acute and chronic administration.
Although the use of capsaicin has dated far back for healing purposes a detailed study shows that it also lowers the inflammation in arthritic rats. Alterations in plasma proteins have been reported in patients with autoinflammatory diseases such as rheumatoid and arthritis. Rats with adjuvant induced arthritis are used as models to find the effect of capsaicin. Arthritis induces in experimental animals by adjuvants show observable symptoms of paw swelling. Capsaicin can effectively scavenge oxygen free radicals generated by macrophages as well as those generated in model systems (Joe et al. 1997). Capsaicin significantly lowered paw inflammation in arthritic rats when given orally for a period of 15 days. All the animals showed a reduction in inflammation after treatment with capsaicin. As described before, capsaicin causes the blockade of nerve conduction, open up cation channels, increase the intracellular concentration of calcium and other ions, and the inhibition of voltage gated calcium channels. The application of capsaicin blocks C-fiber pathway and inactivates substance P release from peripheral nerve endings and due to this neurochemical pathway capsaicin results in the lowering of inflammation.
Currently in the United States, 0.025% and 0.075% topical capsaicin lotions and gels are available as over the counter drugs for external use only. It is used to treat the neuropathic pain of postherpetic neuralgia and for patients suffering painful sores from cancer therapy. It has been useful for chemotherapy patients as chemotherapy works by killing rapidly growing cells in the body. Mucous membranes of the mouth and esophagus are where some of the rapidly growing cells are located. This results in irritating and painful sores, which lead to problems in swallowing and nutrition during treatment. Oral pain affects 40 to 70 percent of patients receiving cancer therapy, impeding speech, eating and overall quality of life (WWW2). Researchers at Yale University School of Medicine devised a candy composed of capsaicin in order to ease mouth pain in cancer patients. (WWW2). These taffy contains different levels of capsaicin to ascertain the right amount of capsaicin release. The taffy is the best candy to add the dosage to because it has no sharp edges to irritate mouth sores. The sugar in the candy inhibits the burn of capsaicin in the mouth and the candy provides the perfect tactile stimulation in the mouth for effectiveness (WWW2).
Surveys show positive results from use of capsaicin for oral pains. All patients reported relief from mucositis pain in which pain was abolished in 2 of 11 patients, with continued use of the candy. About 4-6 candies over 2-4 days were taken. There is a case report in which a patient with pain due to post therapeutic neuralgia applied capsaicin 0.025 ream intraorally. Later after two days all the patients reported relief from mucositis pain in which pain was abolished in 2 of 11 patients, with continued use of the candy. About 4-6 candies over 2-4 days were taken. There is a case report in which a patient with pain due to post therapeutic neuralgia applied capsaicin 0.025 ream intraorally. Later after two days the patient experienced symptomatic improvement and the pain was abolished after four weeks of treatment (WWW1).
Capsaicin is popular among those involved with alternative medicine. Herbalists find it be an excellent therapeutic agent, especially beneficial for the stomach and entire digestive tract. It has shown to be more effective than mustard for congestion of the chest or muscle pains (Weil 1981). Sprinklings of chili pepper in the socks may help cold toes and feet as well. Even to treat cold sores some people gargles with capsicum. The oil of capsicum not only anesthetizes the tooth but also sterilizes tooth cavities while soothing a toothache. From these therapeutic methods, herbalists believe that capsaicin brings blood to the surface of mucous membranes, and increased blood supply is known to promote healing (Weil 1981). Capsaicin purifies the blood, tones the liver, and clears the respiratory tract. With these uses capsaicin seems to be very beneficial and augments one's health.
It has been conjectured that irritant spicy foods may cause cancer. Even excessive ingestion of hot peppers has been suspected to be a risk factor due to injuries in the digestive systems. However, aside from the experimental studies that conduct the risk factors of capsaicin, a case-control study reveals that chili consumption is protective against stomach cancer. Furthermore, the overall frequency of gastric cancer in Mexico, where peppers are more heavily consumed than in any other countries, is in actuality relatively low. Also, the rate of stomach cancer in the United States have been declining despite increased consumption of chili peppers in the past decades (Surh et al. 1997). With this case-control study it seems unlikely that pepper consumption is linked to high risk for stomach cancer in humans. Numerous studies show the positive results of capsaicin. The depletion of substance P makes capsaicin a phenomenal analgesic. Its desensitization mechanism creates advantages for use in numbing painfully sore areas. Also, capsaicin's chemoprotective properties play a role in metabolism of the chemical carcinogens and inhibit DNA binding. It protects against free radicals suggested from the high content of resourceful vitamins. Although, the role of capsaicin suggests that it depletes substance P by destroying a subset of small diameter primary afferent fibers, the overall loss is not devastating. Regeneration of the nerve fibers replaces the subsequently degenerate one and therefore the overall result is a net gain of significant pain relief and protection of cancer and gastrointestinal damages. Therefore, the use of capsaicin whether for the use of protection, analgesic purposes, or for the mere pungency of it should be a rewarding and pleasurable experience.
References
1. Caterina, M.J., Schumacher, M.A., Tominaga, M., Rosen, T.A., Levine, J.D., & Julius, D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389: 816-824 (1997).
2. Joe, B., Rao, U.J.S.P., & Lokesh, B.R. Presence of an acidic glycoprotein in the serum of arthritic rats: Modulation by capsaicin and curcumin. Molecular and Cellular Biochemistry 169: 125-134 (1997).
3. Kang, J.Y., Teng, C.H., Wee, A., & Chen, F.C. Effect of capsaicin and chilli on ethanol induced gastric mucosal injury in the rat. Gut 36: 664-669 (1995).
4. Simone, D.A., Nolano, M., Johnson, T., Wedelschafer-Crabb, G., & Kennedy, W.R. Intradermal Injection of Capsaicin in Humans Produces Degeneration and Subsequent reinnervation of Epidermal Nerve Fibers: Correlation with Sensory Function. The Journal of Neuroscience 18(21): 8947-8954 (1998).
5. Surh, Y-J., Lee, E., & Lee, J.M. Chemoprotective properties of some pungent ingredients present in red pepper and ginger. Mutation Research 402: 259-267 (1998).
6. Surh, Y-J., Lee, C-J., Park, K., Mayne, S.T., Liem, A., & Miller, J.A. Chemoprotective effects of capsaicin and diallyl sulfide against mutagenesis or tumorigenesis by vinyl carbamate and N-nitrosodimethylamine. Carcinogenesis vol. 16 no.10: 2467-2471 (1995).
7. Weil, A. Eating Chilies. Chap. 5 (pp.28-36) The Marriage of the Sun and Moon. Houghton Mifflin Company (1981).
8. WWW1. Capsaicin Use for Oral Pain .
9. WWW2. Hot Pepper Candy Found to Help Chemotherapy Effects .
10. WWW3. Digestive System.
11. WWW4. Peppers and Health: "Are these Buggers Bad For Me? "
12. WWW5. Hot and Spicy vs. Cool and Minty as an example of Organic Structure-Activity Relationship. http://www.chem.umas.edu/genchem/chem102/hotspic.html
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