Capsaicin: A promising multifaceted drug from Capsicum spp.

Evidence-Based Integrative Medicine

Volumn 2, Issue 3, 2005, Pages 147-166

  Prasad, B C N ^a   Shrivastava, Richa ^a   Ravishankar, Gokare A ^a  

^a CENTRAL FOOD TECHNOLOGICAL RESEARCH INSTITUTE   (India)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; ANTIOXIDANT; ANTIRHEUMATIC AGENT; CAPSAICIN;

DRUG METABOLISM; DRUG STRUCTURE; DRUG SYNTHESIS; IN VITRO STUDY; NUCLEOTIDE SEQUENCE; REVIEW;

EID: 33645526811     PISSN: 11762330     EISSN: 11762330     Source Type: Journal    
DOI: 10.2165/01197065-200502030-00006     Document Type: Review

References (184)

1. Clapham DE. Some like it hot: spicing up ion channels. Nature 1997; 389: 783-4
2. Péter SB, Gábor J, László U. The role of the vanilloid (capsaicin) receptor (TRPV1) in physiology and pathology. Eur J Pharmacol 2004; 500 (1-3): 351-69
3. Tewksburry JJ, Nabhan GP. Directed deterrence by capsaicin in chillies. Nature 2001; 412: 403-4
4. Lynn B. Capsaicin: actions on nociceptive C-fibers and therapeutic potential. Pain 1990; 41: 61-91
5. Caterina MJ, Schumacher MA, Tominaga M, et al. The capsaicin receptor: a heat activated ion channel in the pain pathway. Nature 1997; 389: 316-24
6. Purkiss JR. Capsaicin stimulates release of substance P from dorsal root ganglion via two distinct mechanisms. Biochem Soc Trans 1997 Aug; 25 (3): 542S
7. Bennet DJ, Kirby GW. Constitution and biosynthesis of capsaicin. J Chem Soc (C) 1968; 442-6
8. Iwai K, Lee K, Kobashi M, et al. Intracellular localisation of the capsaicinoid synthesizing enzyme in sweet pepper fruits. Agric Biol Chem 1978; 42: 201-2
9. Johnson S, Ravishankar GA, Venkataraman LV. In vitro capsaicin production by immobilized cells and placental tissues of C. annuum grown in liquid medium. Plant Science 1991; 70: 223-9
10. Johnson TS, Ravishankar GA. Precursor biotransformation in immobilized placental tissue of Capsicum frutescens Mill: influence of feeding intermediate metabolites of capsaicinoid metabolites of capsaicin pathway on capsaicin and dihydrocapsaicin accumulation. J Plant Physiol 1996; 147: 481-5
11. Prasad NBC, Gururaj HB, Kumar V, et al. The influence of 8-methyl-nonenoic acid on capsaicin biosynthesis in in vivo and in vitro cell cultures of Capsicum spp. J Agric Food Chem 2006; 54: 1854-9
12. Prasad NBC, Kumar V, Giridhar P, et al., inventors. A spray formulation for enhancing pungency in Capsicum spp. PCT Application PCT/IB04/03197. US Patent Application No. 10/955786. 2003 [patent pending]
13. Sudha G, Ravishankar GA. Influence of calcium modulators on the capsaicin production by cell suspension cultures of Capsicum frutescens L. Curr Sci 2002; 83 (4): 480-4
14. Ravishankar GA, Sarma KS, Venkataraman LV, et al. Effect of nutritional stress on capsaicin production in immobilised cell cultures of Capsicum annuum. Curr Sci 1988; 57 (7): 381-3
15. Curry J, Aluru MR, Mendoza M, et al. Transcripts for possible capsaicinoid biosynthesis genes are differentially accumulated in pungent and non-pungent Capsicum spp. Plant Sci 1999; 148: 47-57
16. Kim M, Kim S, Kim S, et al. Isolation of cDNA clones differentially accumulated in pungent peppers by suppression subtractive hybridization. Mol Cells 2001; 11: 213-9
17. Stewart Jr C, Kang BC, Liu K, et al. The pun1 gene for pungency in pepper encodes a putative acyl transferase. Plant J 2005; 42 (5): 675-88
18. Choi YM, Suh HJ. Pharmacological effect of fermented red pepper. Phytother Res 2004; 18: 884-8
19. Surh YJ, Lee RC, Park KK, et al. Chemoprotective effects of capsaicin and diallyl sulfide against mutagenesis or tumorigenesis by vinyl carbamate and N-nitrosodimethylamine. Carcinogenesis 1995; 16: 2467-71
20. Suzuki T, Fujiwake I, Iwai K. Intracellular localization of capsaicin and its analogues, capsaicinoids in Capsicum fruits 1. Microscopic investigation of the structure of the placenta of Capsicum annuum cv Karayatsubusa. Plant Cell Physiol 1980; 22: 23-32
21. Bors W, Heller W, Michel C, et al. Flavonoids and polyphenols: chemistry and biology. In: Cadenas E, Packer L, editors. Handbook of antioxidants. New York: Dekker, 1996: 409-66
22. Ferrari CKB, Torres EAFS. Biochemical pharmacology of functional foods and prevention of chronic diseases of aging. Biomed Pharmacother 2003; 57: 251-60
23. Harborne JB, Williams CA. Advances in flavonoid research since 1992. Phytochemistry 1992; 55: 481-50
24. Hollman PCH, Katan MB. Dietary flavonoids: intake, health effects and bioavailability. Food Chem Toxicol 1999; 37: 937-42
25. De AK, Ghosh JJ. Studies on capsaicin inhibition of chemically-induced lipid peroxidation in the lung and liver tissues of rat. Phytother Res 1992; 6: 34-7
26. Kogure K, Goto S, Hishimura M, et al. Mechanism of potent antiperoxidative effect of capsaicin. Biochem Biophys Acta 2002; 1573: 84-92
27. Lee CY, Kim M, Yoon SW, et al. Short-term control of capsaicin on blood and oxidative stress of rats in vivo. Phytother Res 2003; 17 (5): 454-8
28. Demirbilek S, Ersoy MO, Demirbilek S, et al. Small-dose capsaicin reduces systemic inflammatory responses in septic rats. Anesth Analg 2004; 99 (5): 1501-7
29. Rosa A, Deiana M, Casu V, et al. Antioxidant activity of capsinoids. J Agric Food Chem 2002; 50 (25): 7396-401
30. Materska M, Perucka I. Antioxidant activity of the main phenolic compounds isolated from hot pepper fruit (Capsicum annuum L.). J Agric Food Chem 2005; 53: 1750-6
31. Jabs T. Reactive oxygen intermediates as mediators of programmed cell death in plants and animals. Biochem Pharmacol 1999; 57: 231-45
32. Crane FL, Sun IL, Crowe RA, et al. Coenzyme Q10, plasma membrane oxidase and growth control. Mol Aspects Med 1994; 15: Suppl.: s1-11
33. Kishi T, Morré DM, Morré DJ. The plasma membrane NADH oxidase of HeLa cells has hydroquinone oxidase activity. Biochim Biophys Acta 1999; 1412: 66-77
34. Morré DJ, Chueh PJ, Morré DM. Capsaicin inhibits preferentially the NADH oxidase and growth of transformed cells in culture. Proc Natl Acad Sci U S A 1995; 92: 1831-5
35. Sun IL, Sun EE, Crane FL, et al. Requirement for coenzyme Q in plasma membrane electron transport. Proc Natl Acad Sci U S A 1992; 89: 11126-30
36. Macho A, Blázquez MV, Navas P, et al. Induction of apoptosis by vanilloid compounds does not require de novo gene transcription and activator protein 1 activity. Cell Growth Differ 1998; 9: 277-86
37. Macho A, Lucena C, Calzado MA, et al. Phorboid 20-homovanillates induce apoptosis through a VR1-independent mechanism. Chem Biol 2000; 7: 483-92
38. Wolvetang EJ, Larm JA, Moutsoulas P, et al. Apoptosis induced by inhibitors of the plasma-membrane NADH-oxidase involves Bcl-2 and calcineurin. Cell Growth Differ 1996; 7: 1315-25
39. Antonio M, Concepción LRS, Nives D, et al. Non-pungent capsaicinoids from sweet pepper: synthesis and evaluation of the chemopreventive and anticancer potential. Eur J Nutr 2003; 42: 2-9
40. Hail N, Lotan R. Examining the role of mitochondrial respiration in vanilloid-induced apoptosis. J Natl Cancer Inst 2002; 94: 1281-92
41. Macho A, Calzado MA, Muñoz Blanco J, et al. Selective induction of apoptosis by capsaicin in transformed cells: the role of reactive oxygen species and calcium. Cell Death Differ 1999; 6: 155-65
42. Bruno M, Brightman AO, Lawrence J, et al. Stimulation of NADH oxidase activity from rat liver plasma membranes by growth factors and hormones is decreased or absent with hepatoma plasma membranes. Biochem J 1992; 284: 625-8
43. Ferguson LR. Antimutagens as cancer chemopreventive agents in the diet. Mutat Res 1994; 307: 395-410
44. Gannett PM, Iversen P, Lawson T. The mechanism of inhibition of cytochrome P450IIEI by dihydrocapsaicin. Bioorg Chem 1990; 18: 185-98
45. Modly CE, Das M, Don PSC, et al. Capsaicin as an in vitro inhibitor of benzo (a)pyrene metabolism and its DNA binding in human and murine keratinocytes. Drug Metab Dispos 1986; 14: 413-6
46. Guengerich FP, Kim DH, Iwasaki M. Role of human P-450 IIEI in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol 1991; 4: 168-79
47. Young JS. Anti-tumor promoting potential of selected spice ingredients with antioxidative and anti-inflammatory activities: a short review. Food Chem Toxicol 2002; 40: 1091-7
48. Prescott SM, Fitzpatrick FA. Cyclooxygenase-2 and carcinogenesis. Biochim Biophys Acta 2000; 1470: 69-78
49. Clementi G, Amico-Rexas M, Caruso A, et al. Effects of CGRP in different models of mouse ear inflammation. Life Sci 1994; 54: 119-24
50. Savitha G, Salimath BP. Effects of capsaicin on phospholipase A2 activity and superoxide generation in macrophages. Nutr Res 1995; 15: 1417-27
51. Kang JY, Teng CT, Wee T, et al. Effect of capsaicin and chilli on ethanol induced gastric mucosal injury in the rat. Gut 1995; 36: 664-9
52. Park JS, Choi MA, Kim BS, et al. Capsaicin protects against ethanol-induced oxidative injury in the gastrointestinal mucosa of rats. Life Sci 2000; 67: 3087-93
53. Park KK, Chun KS, Yook YI, et al. Lack of tumor promoting activity of capsaicin, a principal pungent ingredient of red pepper, in mouse skin carcinogenesis. Anticancer Res 1998; 18: 4201-6
54. Keisuke I, Tomonori N, Kenji Y, et al. Induction of apoptosis in leukemic cells by homovanillic acid derivative, capsaicin, through oxidative stress: implication of phosphorylation of p53 at Ser-15 residue by reactive oxygen species. Cancer Res 2004; 64: 1071-8
55. Richeux F, Cascante M, Ennamany R, et al. Cytotoxicity and genotoxicity of capsaicin in human neuroblastoma cells SHSY-5Y. Arch Toxicol 1999; 73: 403-9
56. Teel RW. Effects of capsaicin on rat liver S9-mediated metabolism and DNA binding of aflatoxin. Nutr Cancer 1991; 15: 27-32
57. Jeong-Ki M, Kyu-Yeon H, Eok-Cheon K, et al. Capsaicin inhibits in vitro and in vivo angiogenesis. Cancer Res 2004; 64: 644-51
58. Archer VE, Jones DW. Capsaicin pepper, cancer and ethnicity. Med Hypotheses 2002; 59: 450-7
59. Dudareva N, Pichersky E, Gershenzon J. Biochemistry of plant volatiles. Plant Physiol 2004; 135 (4): 1893-902
60. Zayachkivska OS, Konturek SJ, Drozdowicz D, et al. Influence of plant-originated gastroprotective and antiulcer substances on gastric mucosal repair. Fiziol Zh 2004; 50: 118-27
61. Benko R, Lazar Z, Undi S, et al. Inhibition of nitric oxide synthesis blocks the inhibitory response to capsaicin in intestinal circular muscle preparations from different species. Life Sci 2005; 76 (24): 2773-82
62. Fujimoto S, Mori M. Characterization of capsaicin-induced, capsazepine-insensitive relaxation of ileal smooth muscle of rats. Eur J Pharmacol 2004; 487: 175-82
63. Caterina MJ, Julius D. The vanilloid receptor: a molecular gateway to the pain pathway. Ann Rev Neurosci 2001; 24: 487-517
64. Anavi-Goffer S, Coutts AA. Cellular distribution of vanilloid VR1 receptor immunoreactivity in the guinea-pig myenteric plexus. Eur J Pharmacol 2003; 458 (1-2): 61-71
65. Benkoa R, Lazara Z, Undia S, et al. Inhibition of nitric oxide synthesis blocks the inhibitory response to capsaicin in intestinal circular muscle preparations from different species. Life Sci 2005; 76 (24): 2773-82
66. Horie S, Yamamoto H, Michael GJ, et al. Protective role of vanilloid receptor type 1 in HCl-induced gastric mucosal lesions in rats. Scand J Gastroenterol 2004; 39 (4): 303-12
67. Aihara E, Hayashi M, Sasaki Y, et al. Mechanisms underlying capsaicin-stimulated secretion in the stomach: comparison with mucosal acidification. J Pharmacol Exp Ther 2005; 315 (1): 423-32
68. Jung J, Hwang SW, Kwak J, et al. Capsaicinoids to the intracellular domain of the capsaicin-activated ion channel. J Neurosci 1999; 19: 529-38
69. Jordt SE, Tominaga M, Julius D. Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc Natl Acad Sci U S A 2000; 97: 8134-9
70. Abdel-Salam A, Debreceni G, Mozsik J, et al. Capsaicin-sensitive afferent sensory nerves in modulating gastric mucosal defense against noxious agents. J Physiol 1999; 93: 443-54
71. Holzer P. Neural emergency system in the stomach. Gastroenterology 1998; 114: 823-39
72. Debreceni A, Abdel-Salam OME, Figler M, et al. Capsaicin increases gastric emptying rate in healthy human subjects measured by 13C-labeled octanoic acid breath. J Physiol Paris 1999; 93: 455-60
73. Yeak KG, Kang YJ, Yap I, et al. Chilli protects against aspirin-induced gastroduodenal mucosal injury in humans. Dig Dis Sci 1995; 40: 580-3
74. Gonzalez R, Dunkel R, Koletzko B, et al. Effect of capsaicin-containing red pepper sauce suspension on upper gastrointestinal motility in healthy volunteers. Dig Dis Sci 1998; 43: 1165-71
75. Mozsik G, Debreceni A, Abdel-Salam OME, et al. Small doses of capsaicin given intragastrically inhibit gastric basal acid secretion in healthy human subjects. J Physiol 1999; 93: 433-6
76. Holzer P. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 1991; 43: 143-201
77. Barthó R, Benkó R, Patacchini G, et al. Effects of capsaicin on visceral smooth muscle: a valuable tool for sensory neurotransmitter identification. Eur J Pharmacol 2004; 500 (1-3): 143-57
78. Zhang L, Jones S, Brody K, et al. Thermosensitive transient receptor potential channels in vagal afferent neurons of the mouse. Am J Physiol 2004; 286 (6): 983-91
79. Avelino A, Cruz C, Nagy I, et al. Vanilloid receptor 1 expression in the rat urinary tract. Neuroscience 2002; 109: 787-98
80. Kato S, Aihara E, Nakamura A, et al. Expression of vanilloid receptors in rat gastric epithelial cells: role in cellular protection. Biochem Pharmacol 2003; 66: 1115-21
81. Ward SM, Bayguinov J, Won KJ, et al. Distribution of the vanilloid receptor (VR1) in the gastrointestinal tract. J Comp Neurol 2003; 465: 121-35
82. Holzer P. Sensory neurone responses to mucosal noxae in the upper gut: relevance to mucosal integrity and gastrointestinal pain. Neurogastroenterol Motil 2002; 4: 459-75
83. Akiba Y, Furukawa O, Guth PH, et al. Sensory pathways and cyclooxygenase regulate mucus gel thickness in rat duodenum. Am J Physiol Gastrointest Liver Physiol 2001; 280: 470-4
84. Yamamoto H, Horie S, Uchida M, et al. Effects of vanilloid receptor agonists and antagonists on gastric antral ulcers in rats. Eur J Pharmacol 2001; 432: 203-10
85. Saeki T, Ohno T, Kamata K, et al. Mild irritant prevents ethanol-induced gastric mucosal microcirculatory disturbances through actions of calcitonin gene-related peptide and PGI2 in rats. Am J Physiol Gastrointest Liver Physiol 2004; 286: 68-75
86. Harada N, Okajima K, Uchiba M, et al. Contribution of capsaicin-sensitive sensory neurons to stress-induced increases in gastric tissue levels of prostaglandins in rats. Am J Physiol Gastrointest Liver Physiol 2003; 285: 1214-24
87. Pothoulakis C, Castagliuolo I, LaMont JT, et al. CP-96,345, a substance P antagonist, inhibits rat intestinal responses to Clostridium difficile toxin A but not cholera toxin. Proc Natl Acad Sci U S A 1994; 91: 947-51
88. McVey DC, Schmid PC, Schmid HH, et al. Endocannabinoids induce ileitis in rats via the capsaicin receptor (VR1). J Pharmacol Exp Ther 2003; 304: 713-22
89. Mang CF, Erbelding D, Kilbinger H. Differential effects of anandamide on acetylcholine release in the guinea-pig ileum mediated via vanilloid and non-CB1 cannabinoid receptors. Br J Pharmacol 2001; 134: 161-7
90. Evangelista S, Tramontana M. Involvement of calcitonin gene-related peptide in rat experimental colitis. J Physiol 1993; 87: 277-80
91. McCafferty DM, Wallace CL, Sharkey KA. Effects of chemical sympathectomy and sensory nerve ablation on experimental colitis in the rat. Am J Physiol 1997; 272: 272-80
92. Hunt RH, Tougas G. Evolving concepts in functional gastrointestinal disorders: promising directions for novel pharmaceutical treatments. Best Pract Res Clin Gastroenterol 2002; 16: 869-83
93. Coelho AM, Vergnolle N, Guiard B, et al. Proteinases and proteinase-activated receptor 2: a possible role to promote visceral hyperalgesia in rats. Gastroenterology 2002; 122: 1035-47
94. Kawao N, Ikeda H, Kitano T, et al. Modulation of capsaicin-evoked visceral pain and referred hyperalgesia by protease-activated receptors 1 and 2. J Pharmacol Sci 2004; 94: 277-85
95. Hillsley K, Grundy D. Serotonin and cholecystokinin activate different populations of rat mesenteric vagal afferents. Neurosci Lett 1998; 255: 63-6
96. Nathan YD, Peng RY, Wang Y, et al. Primary sensory neurons: a common final pathway for inflammation in experimental pancreatitis in rats. Am J Physiol Gastrointest Liver Physiol 2002; 283: 938-46
97. Nathan JD, Patel AA, McVey DC, et al. Capsaicin vanilloid receptor-1 mediates substance P release in experimental pancreatitis. Am, J Physiol Gastrointest Liver Physiol 2001; 281: 1322-8
98. Grady EF, Yoshimi SK, Maa J, et al. Substance P mediates inflammatory oedema in acute pancreatitis via activation of the neurokinin-1 receptor in rats and mice. Br J Pharmacol 2000; 130: 505-12
99. Clayton J. Confusion in the joints. New Sci 1991; 130: 40-3
100. McCarty GM, McCarty DJ. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J Rheumatol 1992; 19: 604-7
101. Joe B, Lokesh BR. Role of capsaicin, curcumin and dietary n-3 fatty acids in lowering the generation of reactive oxygen species in rat peritoneal macrophages. Biochim Biophys Acta 1994; 1224: 255-66
102. Carleson J, Kogner P, Bileviciute I, et al. Effects of capsaicin in temporomandibular joint arthritis in rats. Arch Oral Biol 1997; 42: 869-76
103. Ahmed M, Bjurholm A, Srinivasan GR, et al. Capsaicin effects on substance P and CGRP in rat adjuvant arthritis. Regul Pept 1995; 55: 85-102
104. Colpaert FC, Donnerer J, Lembeck F. Effects of capsaicin on inflammation and on the substance P content of nervous tissues in rats with adjuvant arthritis. Life Sci 1983; 32: 1827-34
105. Cruwys SC, Garrett NE, Kidd BL. Sensory denervation with capsaicin attenuates inflammation and nociception in arthritic rats. Neurosci Lett 1995; 193: 205-7
106. Donnerer J, Amann R, Schuligoi R, et al. Complete recovery by nerve growth factor of neuropeptide content and function in capsaicin-impaired sensory neurons. Brain Res 1996; 741: 103-8
107. Deal CL, Schnitzer TJ, Lipstein E, et al. Treatment of arthritis with topical capsaicin: a double blind trial. Clin Ther 1991; 13: 383-95
108. Simone DA, Baumann TK, LaMotte RH. Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 1989; 38: 99-107
109. Helme RD, Littlejohn GO, Weinstein C. Neurogenic flare responses in chronic rheumatic pain syndromes. Clin Exp Neurol 1987; 23: 91-4
110. Jolliffe VA, Anand P, Kidd BL. Assessment of cutaneous sensory and autonomic axon reflexes in rheumatoid arthritis. Ann Rheum Dis 1995; 54: 251-5
111. Fraenkel L, Bogardus Jr ST, Concato J, et al. Treatment options in knee osteoarthritis: the patient's perspective. Arch Intern Med 2004; 164 (12): 1299-304
112. Blumstein H, Gorevic PD. Rheumatologic illnesses: treatment strategies for older adults. Geriatrics 2005; 60: 28-35
113. Oshita K, Inoue A, Tang HB, et al. CB (1) cannabinoid receptor stimulation modulates transient receptor potential vanilloid receptor 1 activities in calcium influx and substance P Release in cultured rat dorsal root ganglion cells. J Pharmacol Sci 2005; 97 (3): 377-85
114. Rapoport AM, Bigal ME, Tepper SJ, et al. Intranasal medications for the treatment of migraine and cluster headache. CNS Drugs 2004; 18 (10): 671-85
115. Massaad CA, Safieh-Garabedian B, Poole S, et al. Involvement of substance P, CGRP and histamine in the hyperalgesia and cytokine upregulation induced by intraplantar injection of capsaicin in rats. J Neuroimmunol 2004; 153 (1-2): 171-82
116. Nelson AJ, Ragan BG, Bell GW, et al. Capsaicin-based analgesic balm decreases pressor responses evoked by muscle afferents. Med Sci Sports Exerc 2004; 36 (3): 444-50
117. Gottrup H, Bach FW, Jensen TS. Differential effects of peripheral ketamine and lidocaine on skin flux and hyperalgesia induced by intradermal capsaicin in humans. Clin Physiol Funct Imaging 2004; 24 (2): 103-8
118. Mason L, Moore RA, Derry S, et al. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ 2004; 328 (7446): 991
119. Petruzzi M, Lauritano D, De Benedittis M, et al. Systemic capsaicin for burning mouth syndrome: short-term results of a pilot study. J Oral Pathol Med 2004; 33 (2): 111-4
120. Pórszász J, Jancsó N. Studies on the action potentials of sensory nerves in animals desensitized with capsaicine. Acta Physiol Acad Sci Hung 1959; 16: 299-306
121. Jancsó-Gábor A, Szolcsányi J, Jancsó N. Stimulation and desensitization of the hypothalamic heat-sensitive structures by capsaicin in rats. J Physiol 1970; 208: 449-59
122. Jancso G, Kiraly E, Jancso-Gabor A. Pharmacologically induced selective degeneration of chemosensitive primary neurones. Nature 1977; 270: 741-3
123. Maggi R, Patacchini P, Rovero P, et al. Tachykinin receptors and noncholinergic bronchoconstriction in the guinea-pig isolated bronchi. Am Rev Respir Dis 1991; 144: 363-7
124. White DM, Helme RD. Release of substance P from peripheral nerve terminals following electrical stimulation of the sciatic nerve. Brain Res 1985; 336: 27-31
125. Szallasi A, Blumberg PM. Resiniferatoxin and its analogs provide novel insights into the pharmacology of the vanilloid (capsaicin) receptor. Life Sci 1990; 47: 1399-408
126. Nagy I, Rang H. Noxious heat activates all capsaicin-sensitive and also a subpopulation of capsaicin-insensitive dorsal root ganglion neurons. Neuroscience 1999; 88: 995-7
127. Tominaga M, Caterina MJ, Malmberg AB, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 1998; 21 (3): 531-43
128. Catarina MJ, Leffler A, Malmberg AB. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000; 288: 306-13
129. Davis JB, Gray J, Gunthorpe MJ. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 2000; 405: 183-7
130. Avelino A, Dinis P, Charrua P, et al. The endogenous TRPV1 ligand anandamide increases in the rat inflamed urinary bladder and may contribute to inflammatory pain. Soc Neurosci 2003; 33: 608
131. Krause JE, Chenard BL, Cortright DN. Transient receptor potential ion channels as targets for the discovery of pain therapeutics. Curr Opin Investig Drugs 2005; 6 (1): 48-57
132. Schumacher MA, Moff I, Sudanagunta SP, et al. Molecular cloning of an N-terminal splice variant of the capsaicin receptor: loss of N-terminal domain suggests functional divergence among capsaicin receptor subtypes. J Biol Chem 2000; 275: 2756-62
133. Corey DP. New TRP channels in hearing and mechanosensation. Neuron 2003; 39: 585-8
134. Mohapatra DP, Nau C. Desensitization of capsaicin-activated currents in the vanilloid receptor TRPV1 is decreased by the cyclic AMP-dependent protein kinase pathway. J Biol Chem 2003; 278: 50080-90
135. Bhave G, Hu HJ, Glauner KS, et al. Protein kinase C phosphorylation sensitizes but does not activate the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1). Proc Natl Acad Sci U S A 2003; 100: 12480-5
136. 2+/calmodulin-dependent kinase II regulates its vanilloid binding. J Biol Chem 2004; 279: 7048-54
137. Kwak J, Wang MH, Hwang SW, et al. Intracellular ATP increases capsaicin-activated channel activity by interacting with nucleotide-binding domains. J Neurosci 2000; 20: 8298-304
138. Kedei N, Szabo T, Lile JD, et al. Analysis of the native quaternary structure of vanilloid receptor 1. J Biol Chem 2001; 276: 28613-9
139. Kuzhikandathil EV, Wang H, Szabo T, et al. Functional analysis of capsaicin receptor (vanilloid receptor subtype 1) multimerization and agonist responsiveness using a dominant negative mutation. J Neurosci 2001; 21: 8697-706
140. Vennekens R, Voets T, Bindels RJ, et al. Current understanding of mammalian TRP homologues. Cell Calcium 2002; 31: 253-64
141. Chuang YC, Fraser MO, Yu Y, et al. The role of bladder afferent pathways in bladder hyperactivity induced by the intravesical administration of nerve growth factor. J Urol 2001; 165: 975-9
142. Chuang HH, Prescott ED, Kong H, et al. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns (4,5)P2-mediated inhibition. Nature 2001; 411: 957-62
143. Prescott ED, Julius D. A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science 2003; 300: 1284-8
144. Numazaki M, Tominaga T, Takeuchi K, et al. Structural determinant of TRPV1 desensitization interacts with calmodulin. Proc Natl Acad Sci U S A 2003; 100: 8002-6
145. Rosenbaum T, Gordon-Shaag A, Munari M, et al. Ca2+/calmodulin modulates TRPV1 activation by capsaicin. J Gen Physiol 2004; 123: 53-62
146. Morenilla-Palao C, Planells-Cases R, Garcia-Sanz N, et al. Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity. J Biol Chem 2004; 279: 25665-72
147. Trevisani M, Smart MJ, Gunthorpe M, et al. Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat Neurosci 2002; 5: 546-51
148. Ahern GP, Premkumar LS. Voltage-dependent priming of rat vanilloid receptor: effects of agonist and protein kinase C activation. J Physiol 2002; 545: 441-51
149. Babes A, Amuzescu B, Krause U, et al. Cooling inhibits capsaicin-induced currents in cultured rat dorsal root ganglion neurones. Neurosci Lett 2002; 317: 131-4
150. Lopshire JC, Nicol GD. The cAMP transduction cascade mediates the prostaglandin E2 enhancement of the capsaicin-elicited current in rat sensory neurons: whole-cell and single-channel studies. J Neurosci 1998; 18: 6081-92
151. De Petrocellis L, Harrison S, Bisogno T, et al. The vanilloid receptor (VR1)-mediated effects of anandamide are potently enhanced by the cAMP-dependent protein kinase. J Neurochem 2001; 77: 1660-3
152. Rathee PK, Distler C, Obreja O, et al. PKA/AKAP/VR-1 module: a common link of Gs-mediated signaling to thermal hyperalgesia. J Neurosci 2002; 22: 4740-5
153. Carlton SM, Hargett GL. Stereological analysis of Ca (2+)/calmodulin- dependent protein kinase II alpha-containing dorsal root ganglion neurons in the rat: colocalization with isolectin Griffonia simplicifolia, calcitonin gene-related peptide, or vanilloid receptor 1. J Comp Neurol 2002; 448: 102-10
154. Bonnington JK, McNaughton PA. Signalling pathways involved in the sensitisation of mouse nociceptive neurones by nerve growth factor. J Physiol 2003; 551: 433-46
155. Hu HJ, Bhave G, Gereau RW. Prostaglandin and protein kinase A-dependent modulation of vanilloid receptor function by metabotropic glutamate receptor 5: potential mechanism for thermal hyperalgesia. J Neurosci 2002; 22: 7444-52
156. Cesare P, Dekker LV, Sardini A, et al. Specific involvement of PKC-epsilon in sensitization of the neuronal response to painful heat. Neuron 1999; 23: 617-24
157. Sathianathan V, Avelino A, Charrua A, et al. Insulin induces cobalt uptake in a subpopulation of rat cultured primary sensory neurons. Eur J Neurosci 2003; 18: 2477-86
158. Chu CJ, Huang SM, De Petrocellis L, et al. N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia. J Biol Chem 2003; 278: 13633-9
159. Huang SM, Bisogno T, Trevisani M, et al. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc Natl Acad Sci U S A 2002; 99: 8400-5
160. Hwang SW, Cho H, Kwak J, et al. Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci U S A 2000; 97 (11): 6155-60
161. Shin J, Cho H, Hwang SW, et al. Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia. Proc Natl Acad Sci U S A 2002; 99 (15): 10150-5
162. Zygmunt PM, Petersson J, Andersson DA, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 1999; 400: 452-7
163. Gavva NR, Klionsky L, Qu Y, et al. Molecular determinants of vanilloid sensitivity in TRPV1. J Biol Chem 2004; 279: 20283-95
164. Jordt SE, Julius D. Molecular basis for species-specific sensitivity to 'hot' chilli peppers. Cell 2002; 108: 421-30
165. Caterina MJ, Rosen TA, Tominaga M, et al. A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 1999; 398: 436-41
166. Jung SY, Lee SW, Hwang H, et al. Agonist recognition sites in the cytosolic tails of vanilloid receptor 1. J Biol Chem 2002; 277: 44448-54
167. Vlachova V, Teisinger J, Susankova K, et al. Functional role of C-terminal cytoplasmic tail of rat vanilloid receptor 1. J Neurosci 2003; 23: 1340-50
168. Guo A, Vulchanova L, Wang J, et al. Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur J Neurosci 1999; 11: 946-58
169. 2+-release in sensory neurons. J Biol Chem 2004; 279: 16377-87
170. Ahluwalia J, Urbán L, Capogna M, et al. Cannabinoid 1 receptors are expressed in nociceptive primary sensory neurons. Neuroscience 2000; 100: 685-8
171. Ichikawa H, Sugimoto T. The co-expression of P2X3 receptor with VR1 and VRL-1 in the rat trigeminal ganglion. Brain Res 2004; 998: 130-5
172. Tohda C, Sasaki M, Konemura T, et al. Axonal transport of VR1 capsaicin receptor mRNA in primary afferents and its participation in inflammation-induced increase in capsaicin sensitivity. J Neurochem 2001; 76 (6): 1628-35
173. Pare M, Elde E, Mazurkiewicz JE, et al. The Meissner corpuscle revised: a multiafferented mechanoreceptor with nociceptor immunochemical properties. J Neurosci 2001; 21: 7236-46
174. Roberts C, Davis JB, Benham CD. [3H]Resiniferatoxin autoradiography in the CNS of wild-type and TRPV1 null mice defines TRPV1 (VR-1) protein distribution. Brain Res 2004; 995: 176-83
175. Balaban CD, Zhou J, Li HS. Type 1 vanilloid receptor expression by mammalian inner ear ganglion cells. Hear Res 2003; 175: 165-70
176. Zheng J, Dai C, Steyger PS, et al. Vanilloid receptors in hearing: altered cochlear sensitivity by vanilloids and expression of TRPV1 in the organ of corti. J Neurophysiol 2003; 90: 444-55
177. Inoue K, Koizumi S, Fuziwara S, et al. Functional vanilloid receptors in cultured normal human epidermal keratinocytes. Biochem Biophys Res Commun 2002; 291: 124-9
178. Southall MD, Li T, Gharibova LS, et al. Activation of epidermal vanilloid receptor-1 induces release of proinflammatory mediators in human keratinocytes. J Pharmacol Exp Ther 2003; 304: 217-22
179. Chung MK, Lee H, Caterina MJ. Warm temperatures activate TRPV4 in mouse 308 keratinocytes. J Biol Chem 2003; 278: 32037-46
180. Peier AM, Reeve AJ, Andersson DA, et al. A heat-sensitive TRP channel expressed in keratinocytes. Science 2002; 296: 2046-9
181. Birder LA, Nakamura Y, Kiss S, et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci 2002; 5: 856-60
182. Dvorakova M, Kummer W. Transient expression of vanilloid receptor subtype 1 in rat cardiomyocytes during development. Histochem Cell Biol 2001; 116: 223-5
183. Ost D, Roskams T, Van Der AF, et al. Topography of the vanilloid receptor in the human bladder: more than just the nerve fibers. J Urol 2002; 168: 293-7
184. Van Der Aa F, Roskams T, Blyweert W, et al. Interstitial cells in the human prostate: a new therapeutic target? Prostate 2003; 56: 250-5