Capsaicin: Current understanding of its mechanisms and therapy of pain and other pre-clinical and clinical uses

Molecules

Volumn 21, Issue 7, 2016, Pages

  Fattori, Victor ^a   Hohmann, Miriam S N ^a   Rossaneis, Ana C ^a   Pinho Ribeiro, Felipe A ^a   Verri, Waldiceu A ^a  

^a STATE UNIVERSITY OF LONDRINA   (Brazil)

Author keywords

Analgesia; Capsaicinoids; Chili peppers; Desensitization; TRPV1

Indexed keywords

ANALGESIC AGENT; CAPSAICIN; PLANT EXTRACT;

ANIMAL; CHEMISTRY; CLINICAL STUDY; DRUG EFFECTS; DRUG FORMULATION; DRUG REPOSITIONING; HUMAN; ISOLATION AND PURIFICATION; METABOLISM; PAIN; PAIN RECEPTOR; PEPPER; PRECLINICAL STUDY;

ANALGESICS; ANIMALS; CAPSAICIN; CAPSICUM; CLINICAL STUDIES AS TOPIC; DRUG COMPOUNDING; DRUG EVALUATION, PRECLINICAL; DRUG REPOSITIONING; HUMANS; NOCICEPTORS; PAIN; PLANT EXTRACTS;

EID: 84979220886     PISSN: None     EISSN: 14203049     Source Type: Journal    
DOI: 10.3390/molecules21070844     Document Type: Review

References (287)

1. Wolkerstorfer, A.; Handler, N.; Buschmann, H. New approaches to treating pain. Bioorg. Med. Chem. Lett. 2016, 26, 1103-1119. [CrossRef] [PubMed]
2. Yi, P.; Pryzbylkowski, P. Opioid Induced Hyperalgesia. Pain. Med. 2015, 16 (Suppl. S1), S32-S36. [CrossRef] [PubMed]
3. Kaga, H.; Miura, M.; Orito, K. A facile procedure for synthesis of capsaicin. J. Org. Chem. 1989, 54, 3477-3478. [CrossRef]
4. Nelson, E.K.; Dawson, L.E. The constitution of capsaicin, the pungent principle of Capsicum III. J. Am. Chem. Soc. 1923, 45, 2179-2181. [CrossRef]
5. Thiele, R.; Mueller-Seitz, E.; Petz, M. Chili pepper fruits: presumed precursors of fatty acids characteristic for capsaicinoids. J. Agric. Food. Chem. 2008, 56, 4219-4224. [CrossRef] [PubMed]
6. Tewksbury, J.J.; Reagan, K.M.; Machnicki, N.J.; Carlo, T.A.; Haak, D.C.; Penaloza, A.L.; Levey, D.J. Evolutionary ecology of pungency in wild chilies. Proc. Natl. Acad. Sci. USA 2008, 105, 11808-11811. [CrossRef] [PubMed]
7. Veloso, J.; Prego, C.; Varela, M.M.; Carballeira, R.; Bernal, A.; Merino, F.; Diaz, J. Properties of capsaicinoids for the control of fungi and oomycetes pathogenic to pepper. Plant Biol. 2014, 16, 177-185. [CrossRef] [PubMed]
8. Ziglio, A.C.; Gonçalves, D. On the use of capsaicin as a natural preservative against fungal attack on Pinus sp. and Hymenaea sp. woods. Mater. Res. 2014, 17, 271-274. [CrossRef]
9. Thresh, J.C. Isolation of capsaicin. Pharm. J. Trans. 1876, 6, 941-947.
10. Nelson, E.K. The constitution of capsaicin, the pungent principle of capsicum. J. Am. Chem. Soc. 1919, 41, 1115-1121. [CrossRef]
11. Suresh, D.; Srinivasan, K. Tissue distribution & elimination of capsaicin, piperine & curcumin following oral intake in rats. Indian J. Med. Res. 2010, 131, 682-691. [PubMed]
12. National Center for Biotechnology Information. PubChem Compound Database; CID=1548943. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/1548943 (accessed on 17 April 2016).
13. National Center for Biotechnology Information. PubChem Compound Database; CID=107982. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/107982 (accessed on 17 April 2016).
14. National Center for Biotechnology Information. PubChem Compound Database; CID=3084336. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/3084336 (accessed on 17 April 2016).
15. National Center for Biotechnology Information. PubChem Compound Database; CID=168836. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/168836 (accessed on 17 April 2016).
16. National Center for Biotechnology Information. PubChem Compound Database; CID=6442566. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/6442566 (accessed on 17 April 2016).
17. Blum, E.; Mazourek, M.; O'Connell, M.; Curry, J.; Thorup, T.; Liu, K.; Jahn, M.; Paran, I. Molecular mapping of capsaicinoid biosynthesis genes and quantitative trait loci analysis for capsaicinoid content in Capsicum. Theor. Appl. Genet. 2003, 108, 79-86. [CrossRef] [PubMed]
18. Contreras-Padilla, M.; Yahia, E.M. Changes in Capsaicinoids during Development, Maturation, and Senescence of Chile Peppers and Relation with Peroxidase Activity. J. Agric. Food Chem. 1998, 46, 2075-2079. [CrossRef]
19. Reyes-Escogido Mde, L.; Gonzalez-Mondragon, E.G.; Vazquez-Tzompantzi, E. Chemical and pharmacological aspects of capsaicin. Molecules 2011, 16, 1253-1270. [CrossRef] [PubMed]
20. Sutoh, K.; Kobata, K.; Yazawa, S.; Watanabe, T. Capsinoid is biosynthesized from phenylalanine and valine in a non-pungent pepper, Capsicum annuum L. cv. CH-19 sweet. Biosci. Biotechnol. Biochem. 2006, 70, 1513-1516. [CrossRef] [PubMed]
21. Walpole, C.S.; Bevan, S.; Bloomfield, G.; Breckenridge, R.; James, I.F.; Ritchie, T.; Szallasi, A.; Winter, J.; Wrigglesworth, R. Similarities and differences in the structure-activity relationships of capsaicin and resiniferatoxin analogues. J. Med. Chem. 1996, 39, 2939-2952. [CrossRef] [PubMed]
22. Baumann, T.K.; Simone, D.A.; Shain, C.N.; LaMotte, R.H. Neurogenic hyperalgesia: The search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia. J. Neurophysiol. 1991, 66, 212-227. [PubMed]
23. Sluka, K.A.; Willis, W.D. The effects of G-protein and protein kinase inhibitors on the behavioral responses of rats to intradermal injection of capsaicin. Pain 1997, 71, 165-178. [CrossRef]
24. Wood, J.N.; Winter, J.; James, I.F.; Rang, H.P.; Yeats, J.; Bevan, S. Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture. J. Neurosci. 1988, 8, 3208-3220. [PubMed]
25. Oh, U.; Hwang, S.W.; Kim, D. Capsaicin activates a nonselective cation channel in cultured neonatal rat dorsal root ganglion neurons. J. Neurosci. 1996, 16, 1659-1667. [PubMed]
26. 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 1997, 389, 816-824. [PubMed]
27. Wang, S.; Joseph, J.; Diatchenko, L.; Ro, J.Y.; Chung, M.K. Agonist-dependence of functional properties for common nonsynonymous variants of human transient receptor potential vanilloid 1. Pain 2016, 157, 1515-1524. [CrossRef] [PubMed]
28. Caterina, M.J.; Leffler, A.; Malmberg, A.B.; Martin, W.J.; Trafton, J.; Petersen-Zeitz, K.R.; Koltzenburg, M.; Basbaum, A.I.; Julius, D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000, 288, 306-313. [CrossRef] [PubMed]
29. Szolcsanyi, J. A pharmacological approach to elucidation of the role of different nerve fibres and receptor endings in mediation of pain. J. Physiol. 1977, 73, 251-259.
30. Zou, X.; Lin, Q.; Willis, W.D. Role of protein kinase A in phosphorylation of NMDA receptor 1 subunits in dorsal horn and spinothalamic tract neurons after intradermal injection of capsaicin in rats. Neuroscience 2002, 115, 775-786. [CrossRef]
31. Zou, X.; Lin, Q.; Willis, W.D. Effect of protein kinase C blockade on phosphorylation of NR1 in dorsal horn and spinothalamic tract cells caused by intradermal capsaicin injection in rats. Brain. Res. 2004, 1020, 95-105. [CrossRef] [PubMed]
32. Sweitzer, S.M.; Peters, M.C.; Ma, J.Y.; Kerr, I.; Mangadu, R.; Chakravarty, S.; Dugar, S.; Medicherla, S.; Protter, A.A.; Yeomans, D.C. Peripheral and central p38 MAPK mediates capsaicin-induced hyperalgesia. Pain 2004, 111, 278-285. [CrossRef] [PubMed]
33. Sun, R.Q.; Lawand, N.B.; Willis, W.D. The role of calcitonin gene-related peptide (CGRP) in the generation and maintenance of mechanical allodynia and hyperalgesia in rats after intradermal injection of capsaicin. Pain 2003, 104, 201-208. [CrossRef]
34. Salvemini, D.; Little, J.W.; Doyle, T.; Neumann, W.L. Roles of reactive oxygen and nitrogen species in pain. Free Radic. Biol. Med. 2011, 51, 951-966. [CrossRef] [PubMed]
35. Fattori, V.; Pinho-Ribeiro, F.A.; Borghi, S.M.; Alves-Filho, J.C.; Cunha, T.M.; Cunha, F.Q.; Casagrande, R.; Verri, W.A. Curcumin inhibits superoxide anion-induced pain-like behavior and leukocyte recruitment by increasing Nrf2 expression and reducing NF-kappaB activation. Inflamm. Res. 2015, 64, 993-1003. [CrossRef] [PubMed]
36. Thannickal, V.J.; Fanburg, B.L. Reactive oxygen species in cell signaling. Am. J. Physiol. Lung. Cell. Mol. Physiol. 2000, 279, L1005-1028. [PubMed]
37. Lee, I.; Kim, H.K.; Kim, J.H.; Chung, K.; Chung, J.M. The role of reactive oxygen species in capsaicin-induced mechanical hyperalgesia and in the activities of dorsal horn neurons. Pain 2007, 133, 9-17. [CrossRef] [PubMed]
38. Pang, Z.; Sakamoto, T.; Tiwari, V.; Kim, Y.S.; Yang, F.; Dong, X.; Guler, A.D.; Guan, Y.; Caterina, M.J. Selective keratinocyte stimulation is sufficient to evoke nociception in mice. Pain 2015, 156, 656-665. [CrossRef] [PubMed]
39. Laird, J.M.; Martinez-Caro, L.; Garcia-Nicas, E.; Cervero, F. A new model of visceral pain and referred hyperalgesia in the mouse. Pain 2001, 92, 335-342. [CrossRef]
40. Akbar, A.; Yiangou, Y.; Facer, P.; Walters, J.R.; Anand, P.; Ghosh, S. Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain. Gut 2008, 57, 923-929. [CrossRef] [PubMed]
41. Lapointe, T.K.; Basso, L.; Iftinca, M.C.; Flynn, R.; Chapman, K.; Dietrich, G.; Vergnolle, N.; Altier, C. TRPV1 sensitization mediates postinflammatory visceral pain following acute colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2015, 309, G87-G99. [CrossRef] [PubMed]
42. Evangelista, S. Capsaicin receptor as target of calcitonin gene-related peptide in the gut. Prog. Drug. Res. 2014, 68, 259-276. [PubMed]
43. Yee, J.R.; Kenkel, W.; Caccaviello, J.C.; Gamber, K.; Simmons, P.; Nedelman, M.; Kulkarni, P.; Ferris, C.F. Identifying the integrated neural networks involved in capsaicin-induced pain using fMRI in awake TRPV1 knockout and wild-type rats. Front. Syst. Neurosci. 2015, 9. [CrossRef] [PubMed]
44. Jurik, A.; Ressle, A.; Schmid, R.M.; Wotjak, C.T.; Thoeringer, C.K. Supraspinal TRPV1 modulates the emotional expression of abdominal pain. Pain 2014, 155, 2153-2160. [CrossRef] [PubMed]
45. Walsh, D.A.; Mapp, P.I.; Kelly, S. Calcitonin gene-related peptide in the joint: contributions to pain and inflammation. Br. J. Clin. Pharmacol. 2015, 80, 965-978. [CrossRef] [PubMed]
46. Bullock, C.M.; Wookey, P.; Bennett, A.; Mobasheri, A.; Dickerson, I.; Kelly, S. Peripheral calcitonin gene-related peptide receptor activation and mechanical sensitization of the joint in rat models of osteoarthritis pain. Arthritis Rheumatol. 2014, 66, 2188-2200. [CrossRef] [PubMed]
47. Binshtok, A.M.; Bean, B.P.; Woolf, C.J. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 2007, 449, 607-610. [CrossRef] [PubMed]
48. Chung, M.K.; Guler, A.D.; Caterina, M.J. TRPV1 shows dynamic ionic selectivity during agonist stimulation. Nat. Neurosci. 2008, 11, 555-564. [CrossRef] [PubMed]
49. Koda, K.; Hyakkoku, K.; Ogawa, K.; Takasu, K.; Imai, S.; Sakurai, Y.; Fujita, M.; Ono, H.; Yamamoto, M.; Fukuda, I.; et al. Sensitization of TRPV1 by protein kinase C in rats with mono-iodoacetate-induced joint pain. Osteoarthr. Cartil. 2016. [CrossRef] [PubMed]
50. Yang, F.; Xiao, X.; Cheng, W.; Yang, W.; Yu, P.; Song, Z.; Yarov-Yarovoy, V.; Zheng, J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel. Nat. Chem. Biol. 2015, 11, 518-524. [CrossRef] [PubMed]
51. Elokely, K.; Velisetty, P.; Delemotte, L.; Palovcak, E.; Klein, M.L.; Rohacs, T.; Carnevale, V. Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin. Proc. Natl. Acad. Sci. USA 2016, 113, E137-E145. [CrossRef] [PubMed]
52. Wrigglesworth, R.; Walpole, C.S.; Bevan, S.; Campbell, E.A.; Dray, A.; Hughes, G.A.; James, I.; Masdin, K.J.; Winter, J. Analogues of capsaicin with agonist activity as novel analgesic agents: Structure-activity studies. 4. Potent, orally active analgesics. J. Med. Chem. 1996, 39, 4942-4951. [CrossRef] [PubMed]
53. Akopian, A.N. Regulation of nociceptive transmission at the periphery via TRPA1-TRPV1 interactions. Curr. Pharm. Biotechnol. 2011, 12, 89-94. [CrossRef] [PubMed]
54. Fischer, M.J.; Balasuriya, D.; Jeggle, P.; Goetze, T.A.; McNaughton, P.A.; Reeh, P.W.; Edwardson, J.M. Direct evidence for functional TRPV1/TRPA1 heteromers. Pflugers Arch. 2014, 466, 2229-2241. [CrossRef] [PubMed]
55. 2+-gating of Transient Receptor Potential channels in trigeminal sensory neurons and peripheral nerve terminals. Pharmacol. Res. 2015, 100, 101-116. [CrossRef] [PubMed]
56. Weng, H.J.; Patel, K.N.; Jeske, N.A.; Bierbower, S.M.; Zou, W.; Tiwari, V.; Zheng, Q.; Tang, Z.; Mo, G.C.; Wang, Y.; et al. Tmem100 Is a Regulator of TRPA1-TRPV1 Complex and Contributes to Persistent Pain. Neuron 2015, 85, 833-846. [CrossRef] [PubMed]
57. Salas, M.M.; Hargreaves, K.M.; Akopian, A.N. TRPA1-mediated responses in trigeminal sensory neurons: Interaction between TRPA1 and TRPV1. Eur. J. Neurosci. 2009, 29, 1568-1578. [CrossRef] [PubMed]
58. Spahn, V.; Stein, C.; Zollner, C. Modulation of transient receptor vanilloid 1 activity by transient receptor potential ankyrin 1. Mol. Pharmacol. 2014, 85, 335-344. [CrossRef] [PubMed]
59. Pinho-Ribeiro, F.A.; Zarpelon, A.C.; Fattori, V.; Manchope, M.F.; Mizokami, S.S.; Casagrande, R.; Verri, W.A. Naringenin reduces inflammatory pain in mice. Neuropharmacology 2016, 105, 508-519. [CrossRef] [PubMed]
60. Borghi, S.M.; Carvalho, T.T.; Staurengo-Ferrari, L.; Hohmann, M.S.; Pinge-Filho, P.; Casagrande, R.; Verri, W.A. Vitexin inhibits inflammatory pain in mice by targeting TRPV1, oxidative stress, and cytokines. J. Nat. Prod. 2013, 76, 1141-1149. [CrossRef] [PubMed]
61. Pinho-Ribeiro, F.A.; Hohmann, M.S.; Borghi, S.M.; Zarpelon, A.C.; Guazelli, C.F.; Manchope, M.F.; Casagrande, R.; Verri, W.A. Protective effects of the flavonoid hesperidin methyl chalcone in inflammation and pain in mice: Role of TRPV1, oxidative stress, cytokines and NF-kappaB. Chem. Biol. Interact. 2015, 228, 88-99. [CrossRef] [PubMed]
62. Rossato, M.F.; Trevisan, G.; Walker, C.I.; Klafke, J.Z.; de Oliveira, A.P.; Villarinho, J.G.; Zanon, R.B.; Royes, L.F.; Athayde, M.L.; Gomez, M.V.; et al. Eriodictyol: A flavonoid antagonist of the TRPV1 receptor with antioxidant activity. Biochem. Pharmacol. 2011, 81, 544-551. [CrossRef] [PubMed]
63. Martinez, A.L.; Gonzalez-Trujano, M.E.; Chavez, M.; Pellicer, F.; Moreno, J.; Lopez-Munoz, F.J. Hesperidin produces antinociceptive response and synergistic interaction with ketorolac in an arthritic gout-type pain in rats. Pharmacol. Biochem. Behav. 2011, 97, 683-689. [CrossRef] [PubMed]
64. Shin, J.H.; Lee, C.W.; Oh, S.J.; Yun, J.; Lee, K.; Park, S.K.; Kim, H.M.; Han, S.B.; Kim, Y.; Kim, H.C.; et al. Protective effect of silymarin against ethanol-induced gastritis in rats: role of sulfhydryls, nitric oxide and gastric sensory afferents. Food Chem. Toxicol. 2013, 55, 353-357. [CrossRef] [PubMed]
65. Trevisan, G.; Rossato, M.F.; Walker, C.I.; Klafke, J.Z.; Rosa, F.; Oliveira, S.M.; Tonello, R.; Guerra, G.P.; Boligon, A.A.; Zanon, R.B.; et al. Identification of the plant steroid alpha-spinasterol as a novel transient receptor potential vanilloid 1 antagonist with antinociceptive properties. J. Pharmacol. Exp. Ther. 2012, 343, 258-269. [CrossRef] [PubMed]
66. Zhi, L.; Dong, L.; Kong, D.; Sun, B.; Sun, Q.; Grundy, D.; Zhang, G.; Rong, W. Curcumin acts via transient receptor potential vanilloid-1 receptors to inhibit gut nociception and reverses visceral hyperalgesia. Neurogastroenterol. Motil. 2013, 25, e429-e440. [CrossRef] [PubMed]
67. Aggarwal, B.B.; Harikumar, K.B. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int. J. Biochem. Cell Biol. 2009, 41, 40-59. [CrossRef] [PubMed]
68. Yeon, K.Y.; Kim, S.A.; Kim, Y.H.; Lee, M.K.; Ahn, D.K.; Kim, H.J.; Kim, J.S.; Jung, S.J.; Oh, S.B. Curcumin produces an antihyperalgesic effect via antagonism of TRPV1. J. Dent. Res. 2010, 89, 170-174. [CrossRef] [PubMed]
69. Cui, M.; Gosu, V.; Basith, S.; Hong, S.; Choi, S. Polymodal Transient Receptor Potential Vanilloid Type 1 Nocisensor: Structure, Modulators, and Therapeutic Applications. Adv. Protein Chem. Struct. Biol. 2016, 104, 81-125. [PubMed]
70. Brandt, M.R.; Beyer, C.E.; Stahl, S.M. TRPV1 Antagonists and Chronic Pain: Beyond Thermal Perception. Pharmaceuticals 2012, 5, 114-132. [CrossRef] [PubMed]
71. Chizh, B.A.; O'Donnell, M.B.; Napolitano, A.; Wang, J.; Brooke, A.C.; Aylott, M.C.; Bullman, J.N.; Gray, E.J.; Lai, R.Y.; Williams, P.M.; et al. The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans. Pain 2007, 132, 132-141. [CrossRef] [PubMed]
72. Gavva, N.R.; Treanor, J.J.; Garami, A.; Fang, L.; Surapaneni, S.; Akrami, A.; Alvarez, F.; Bak, A.; Darling, M.; Gore, A.; et al. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 2008, 136, 202-210. [CrossRef] [PubMed]
73. Simone, D.A.; Ngeow, J.Y.; Putterman, G.J.; LaMotte, R.H. Hyperalgesia to heat after intradermal injection of capsaicin. Brain Res. 1987, 418, 201-203. [CrossRef]
74. Nagy, J.I.; van der Kooy, D. Effects of neonatal capsaicin treatment on nociceptive thresholds in the rat. J. Neurosci. 1983, 3, 1145-1150. [PubMed]
75. Kissin, I. Vanilloid-induced conduction analgesia: Selective, dose-dependent, long-lasting, with a low level of potential neurotoxicity. Anesth. Analg. 2008, 107, 271-281. [CrossRef] [PubMed]
76. Palazzo, E.; de Novellis, V.; Marabese, I.; Cuomo, D.; Rossi, F.; Berrino, L.; Rossi, F.; Maione, S. Interaction between vanilloid and glutamate receptors in the central modulation of nociception. Eur. J. Pharmacol. 2002, 439, 69-75. [CrossRef]
77. Szallasi, A.; Blumberg, P.M. Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol. Rev. 1999, 51, 159-212. [PubMed]
78. Lee, S.S.; Sohn, Y.W.; Yoo, E.S.; Kim, K.H. Neurotoxicity and long lasting analgesia induced by capsaicinoids. J. Toxicol. Sci. 1991, 16 (Suppl. 1), 3-20. [CrossRef] [PubMed]
79. Burks, T.F.; Buck, S.H.; Miller, M.S. Mechanisms of depletion of substance P by capsaicin. Fed. Proc. 1985, 44, 2531-2534. [PubMed]
80. Comunanza, V.; Carbone, E.; Marcantoni, A.; Sher, E.; Ursu, D. Calcium-dependent inhibition of T-type calcium channels by TRPV1 activation in rat sensory neurons. Pflugers Arch. 2011, 462, 709-722. [CrossRef] [PubMed]
81. 2+/calmodulin modulates TRPV1 activation by capsaicin. J. Gen. Physiol. 2004, 123, 53-62. [CrossRef] [PubMed]
82. Koplas, P.A.; Rosenberg, R.L.; Oxford, G.S. The role of calcium in the desensitization of capsaicin responses in rat dorsal root ganglion neurons. J. Neurosci. 1997, 17, 3525-3537. [PubMed]
83. Lishko, P.V.; Procko, E.; Jin, X.; Phelps, C.B.; Gaudet, R. The ankyrin repeats of TRPV1 bind multiple ligands and modulate channel sensitivity. Neuron 2007, 54, 905-918. [CrossRef] [PubMed]
84. 2+-dependent desensitization in the vanilloid receptor TRPV1 by calcineurin and cAMP-dependent protein kinase. J. Biol. Chem. 2005, 280, 13424-13432. [CrossRef] [PubMed]
85. Wu, Z.Z.; Chen, S.R.; Pan, H.L. Transient receptor potential vanilloid type 1 activation down-regulates voltage-gated calcium channels through calcium-dependent calcineurin in sensory neurons. J. Biol. Chem. 2005, 280, 18142-18151. [CrossRef] [PubMed]
86. Borbiro, I.; Badheka, D.; Rohacs, T. Activation of TRPV1 channels inhibits mechanosensitive Piezo channel activity by depleting membrane phosphoinositides. Sci. Signal. 2015, 8. [CrossRef] [PubMed]
87. Hiura, A.; Ishizuka, H. Changes in features of degenerating primary sensory neurons with time after capsaicin treatment. Acta Neuropathol. 1989, 78, 35-46. [CrossRef] [PubMed]
88. Chung, J.M.; Paik, K.S.; Kim, J.S.; Nam, S.C.; Kim, K.J.; Oh, U.T.; Hasegawa, T.; Chung, K.; Willis, W.D. Chronic effects of topical application of capsaicin to the sciatic nerve on responses of primate spinothalamic neurons. Pain 1993, 53, 311-321. [CrossRef]
89. Simone, D.A.; Nolano, M.; Johnson, T.; Wendelschafer-Crabb, G.; Kennedy, W.R. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J. Neurosci. 1998, 18, 8947-8959. [PubMed]
90. Holzer, P.; Jurna, I.; Gamse, R.; Lembeck, F. Nociceptive threshold after neonatal capsaicin treatment. Eur. J. Pharmacol. 1979, 58, 511-514. [CrossRef]
91. Shin, C.Y.; Shin, J.; Kim, B.M.; Wang, M.H.; Jang, J.H.; Surh, Y.J.; Oh, U. Essential role of mitochondrial permeability transition in vanilloid receptor 1-dependent cell death of sensory neurons. Mol. Cell Neurosci. 2003, 24, 57-68. [CrossRef]
92. 2+-binding protein calretinin. Biochim. Biophys. Acta 2013, 1833, 1680-1691. [CrossRef] [PubMed]
93. Baamonde, A.; Lastra, A.; Juarez, L.; Hidalgo, A.; Menendez, L. TRPV1 desensitisation and endogenous vanilloid involvement in the enhanced analgesia induced by capsaicin in inflamed tissues. Brain Res. Bull. 2005, 67, 476-481. [CrossRef] [PubMed]
94. Menendez, L.; Lastra, A.; Hidalgo, A.; Baamonde, A. The analgesic effect induced by capsaicin is enhanced in inflammatory states. Life Sci. 2004, 74, 3235-3244. [CrossRef] [PubMed]
95. Orliac, M.L.; Peroni, R.N.; Abramoff, T.; Neuman, I.; Podesta, E.J.; Adler-Graschinsky, E. Increases in vanilloid TRPV1 receptor protein and CGRP content during endotoxemia in rats. Eur. J. Pharmacol. 2007, 566, 145-152. [CrossRef] [PubMed]
96. Gear, R.W.; Aley, K.O.; Levine, J.D. Pain-induced analgesia mediated by mesolimbic reward circuits. J. Neurosci. 1999, 19, 7175-7181. [PubMed]
97. Tambeli, C.H.; Levine, J.D.; Gear, R.W. Centralization of noxious stimulus-induced analgesia (NSIA) is related to activity at inhibitory synapses in the spinal cord. Pain 2009, 143, 228-232. [CrossRef] [PubMed]
98. Lee, J.S.; Kim, S.G.; Kim, H.K.; Baek, S.Y.; Kim, C.M. Acute effects of capsaicin on proopioimelanocortin mRNA levels in the arcuate nucleus of Sprague-Dawley rats. Psychiatry Investig. 2012, 9, 187-190. [CrossRef] [PubMed]
99. Eimerl, D.; Papir-Kricheli, D. Epidural capsaicin produces prolonged segmental analgesia in the rat. Exp. Neurol. 1987, 97, 169-178. [CrossRef]
100. Szabo, T.; Olah, Z.; Iadarola, M.J.; Blumberg, P.M. Epidural resiniferatoxin induced prolonged regional analgesia to pain. Brain Res. 1999, 840, 92-98. [CrossRef]
101. Yaksh, T.L.; Farb, D.H.; Leeman, S.E.; Jessell, T.M. Intrathecal capsaicin depletes substance P in the rat spinal cord and produces prolonged thermal analgesia. Science 1979, 206, 481-483. [CrossRef] [PubMed]
102. v3.2 calcium channels: The key protagonist in the supraspinal effect of paracetamol. Pain 2014, 155, 764-772. [CrossRef] [PubMed]
103. McGaraughty, S.; Chu, K.L.; Bitner, R.S.; Martino, B.; El Kouhen, R.; Han, P.; Nikkel, A.L.; Burgard, E.C.; Faltynek, C.R.; Jarvis, M.F. Capsaicin infused into the PAG affects rat tail flick responses to noxious heat and alters neuronal firing in the RVM. J. Neurophysiol. 2003, 90, 2702-2710. [CrossRef] [PubMed]
104. Mohammadi-Farani, A.; Sahebgharani, M.; Sepehrizadeh, Z.; Jaberi, E.; Ghazi-Khansari, M. Diabetic thermal hyperalgesia: Role of TRPV1 and CB1 receptors of periaqueductal gray. Brain Res. 2010, 1328, 49-56. [CrossRef] [PubMed]
105. Starowicz, K.; Maione, S.; Cristino, L.; Palazzo, E.; Marabese, I.; Rossi, F.; de Novellis, V.; di Marzo, V. Tonic endovanilloid facilitation of glutamate release in brainstem descending antinociceptive pathways. J. Neurosci. 2007, 27, 13739-13749. [CrossRef] [PubMed]
106. Liao, H.T.; Lee, H.J.; Ho, Y.C.; Chiou, L.C. Capsaicin in the periaqueductal gray induces analgesia via metabotropic glutamate receptor-mediated endocannabinoid retrograde disinhibition. Br. J. Pharmacol. 2011, 163, 330-345. [CrossRef] [PubMed]
107. Maione, S.; Starowicz, K.; Cristino, L.; Guida, F.; Palazzo, E.; Luongo, L.; Rossi, F.; Marabese, I.; de Novellis, V.; di Marzo, V. Functional interaction between TRPV1 and mu-opioid receptors in the descending antinociceptive pathway activates glutamate transmission and induces analgesia. J. Neurophysiol. 2009, 101, 2411-2422. [CrossRef] [PubMed]
108. Silva, M.; Martins, D.; Charrua, A.; Piscitelli, F.; Tavares, I.; Morgado, C.; Di Marzo, V. Endovanilloid control of pain modulation by the rostroventromedial medulla in an animal model of diabetic neuropathy. Neuropharmacology 2016, 107, 49-57. [CrossRef] [PubMed]
109. Kingery, W.S. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 1997, 73, 123-139. [CrossRef]
110. Robbins, W.R.; Staats, P.S.; Levine, J.; Fields, H.L.; Allen, R.W.; Campbell, J.N.; Pappagallo, M. Treatment of intractable pain with topical large-dose capsaicin: Preliminary report. Anesth. Analg. 1998, 86, 579-583. [CrossRef] [PubMed]
111. Ellison, N.; Loprinzi, C.L.; Kugler, J.; Hatfield, A.K.; Miser, A.; Sloan, J.A.; Wender, D.B.; Rowland, K.M.; Molina, R.; Cascino, T.L.; et al. Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J. Clin. Oncol. 1997, 15, 2974-2980. [PubMed]
112. Zis, P.; Apsokardos, A.; Isaia, C.; Sykioti, P.; Vadalouca, A. Posttraumatic and postsurgical neuropathic pain responsive to treatment with capsaicin 8% topical patch. Pain Phys. 2014, 17, E213-E218.
113. Watson, C.P.; Evans, R.J.; Watt, V.R.; Birkett, N. Post-herpetic neuralgia: 208 cases. Pain 1988, 35, 289-297. [CrossRef]
114. Watson, C.P.; Tyler, K.L.; Bickers, D.R.; Millikan, L.E.; Smith, S.; Coleman, E. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin. Ther. 1993, 15, 510-526. [CrossRef] [PubMed]
115. Kiani, J.; Sajedi, F.; Nasrollahi, S.A.; Esna-Ashari, F. A randomized clinical trial of efficacy and safety of the topical clonidine and capsaicin in the treatment of painful diabetic neuropathy. J. Res. Med. Sci. 2015, 20, 359-363. [PubMed]
116. Burness, C.B.; McCormack, P.L. Capsaicin 8% Patch: A Review in Peripheral Neuropathic Pain. Drugs 2016, 76, 123-134. [CrossRef] [PubMed]
117. Fusco, B.M.; Marabini, S.; Maggi, C.A.; Fiore, G.; Geppetti, P. Preventative effect of repeated nasal applications of capsaicin in cluster headache. Pain 1994, 59, 321-325. [CrossRef]
118. Nolano, M.; Simone, D.A.; Wendelschafer-Crabb, G.; Johnson, T.; Hazen, E.; Kennedy, W.R. Topical capsaicin in humans: Parallel loss of epidermal nerve fibers and pain sensation. Pain 1999, 81, 135-145. [CrossRef]
119. Backonja, M.M.; Malan, T.P.; Vanhove, G.F.; Tobias, J.K.; Group, C.S. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: A randomized, double-blind, controlled study with an open-label extension. Pain Med. 2010, 11, 600-608. [CrossRef] [PubMed]
120. Irving, G.A.; Backonja, M.M.; Dunteman, E.; Blonsky, E.R.; Vanhove, G.F.; Lu, S.P.; Tobias, J.; Group, N.C.S. A multicenter, randomized, double-blind, controlled study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia. Pain Med. 2011, 12, 99-109. [CrossRef] [PubMed]
121. Berger, A.; Henderson, M.; Nadoolman, W.; Duffy, V.; Cooper, D.; Saberski, L.; Bartoshuk, L. Oral capsaicin provides temporary relief for oral mucositis pain secondary to chemotherapy/radiation therapy. J. Pain Symptom Manag. 1995, 10, 243-248. [CrossRef]
122. Turnbull, J.H.; Gebauer, S.L.; Miller, B.L.; Barbaro, N.M.; Blanc, P.D.; Schumacher, M.A. Cutaneous nerve transection for the management of intractable upper extremity pain caused by invasive squamous cell carcinoma. J. Pain Symptom Manag. 2011, 42, 126-133. [CrossRef] [PubMed]
123. Kim, H.Y.; Kim, K.; Li, H.Y.; Chung, G.; Park, C.K.; Kim, J.S.; Jung, S.J.; Lee, M.K.; Ahn, D.K.; Hwang, S.J.; et al. Selectively targeting pain in the trigeminal system. Pain 2010, 150, 29-40. [CrossRef] [PubMed]
124. Peters, C.M.; Ririe, D.; Houle, T.T.; Aschenbrenner, C.A.; Eisenach, J.C. Nociceptor-selective peripheral nerve block induces delayed mechanical hypersensitivity and neurotoxicity in rats. Anesthesiology 2014, 120, 976-986. [CrossRef] [PubMed]
125. McCleane, G. Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: A randomized, double-blind, placebo-controlled study. Br. J. Clin. Pharmacol. 2000, 49, 574-579. [CrossRef] [PubMed]
126. Kopelman, P.G. Obesity as a medical problem. Nature 2000, 404, 635-643. [PubMed]
127. Ogden, C.L.; Carroll, M.D.; Curtin, L.R.; McDowell, M.A.; Tabak, C.J.; Flegal, K.M. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 2006, 295, 1549-1555. [CrossRef] [PubMed]
128. Yu, Q.; Wang, Y.; Yu, Y.; Li, Y.; Zhao, S.; Chen, Y.; Waqar, A.B.; Fan, J.; Liu, E. Expression of TRPV1 in rabbits and consuming hot pepper affects its body weight. Mol. Biol. Rep. 2012, 39, 7583-7589. [CrossRef] [PubMed]
129. Kawada, T.; Hagihara, K.; Iwai, K. Effects of capsaicin on lipid metabolism in rats fed a high fat diet. J. Nutr. 1986, 116, 1272-1278. [PubMed]
130. Ludy, M.J.; Moore, G.E.; Mattes, R.D. The effects of capsaicin and capsiate on energy balance: Critical review and meta-analyses of studies in humans. Chem. Senses 2012, 37, 103-121. [CrossRef] [PubMed]
131. Ludy, M.J.; Mattes, R.D. The effects of hedonically acceptable red pepper doses on thermogenesis and appetite. Physiol. Behav. 2011, 102, 251-258. [CrossRef] [PubMed]
132. Westerterp-Plantenga, M.S.; Smeets, A.; Lejeune, M.P. Sensory and gastrointestinal satiety effects of capsaicin on food intake. Int. J. Obes. 2005, 29, 682-688. [CrossRef] [PubMed]
133. Yoshioka, M.; St-Pierre, S.; Drapeau, V.; Dionne, I.; Doucet, E.; Suzuki, M.; Tremblay, A. Effects of red pepper on appetite and energy intake. Br. J. Nutr. 1999, 82, 115-123. [PubMed]
134. Smeets, A.J.; Janssens, P.L.; Westerterp-Plantenga, M.S. Addition of capsaicin and exchange of carbohydrate with protein counteract energy intake restriction effects on fullness and energy expenditure. J. Nutr. 2013, 143, 442-447. [CrossRef] [PubMed]
135. Reinbach, H.C.; Smeets, A.; Martinussen, T.; Moller, P.; Westerterp-Plantenga, M.S. Effects of capsaicin, green tea and CH-19 sweet pepper on appetite and energy intake in humans in negative and positive energy balance. Clin. Nutr. 2009, 28, 260-265. [CrossRef] [PubMed]
136. Watanabe, T.; Kawada, T.; Kurosawa, M.; Sato, A.; Iwai, K. Adrenal sympathetic efferent nerve and catecholamine secretion excitation caused by capsaicin in rats. Am. J. Physiol. 1988, 255, E23-E27. [PubMed]
137. Watanabe, T.; Kawada, T.; Yamamoto, M.; Iwai, K. Capsaicin, a pungent principle of hot red pepper, evokes catecholamine secretion from the adrenal medulla of anesthetized rats. Biochem. Biophys. Res. Commun. 1987, 142, 259-264. [CrossRef]
138. Russek, M.; Vega, C.; Barrera, J.; Soto-Mora, L.M.; Lanzagorta, A.; Racotta, R. Anorexia elicited by different catecholamines in rats. Appetite 1987, 9, 119-126. [CrossRef]
139. Smeets, A.J.; Westerterp-Plantenga, M.S. The acute effects of a lunch containing capsaicin on energy and substrate utilisation, hormones, and satiety. Eur. J. Nutr. 2009, 48, 229-234. [CrossRef] [PubMed]
140. Janssens, P.L.; Hursel, R.; Westerterp-Plantenga, M.S. Capsaicin increases sensation of fullness in energy balance, and decreases desire to eat after dinner in negative energy balance. Appetite 2014, 77, 44-49. [CrossRef] [PubMed]
141. Matsumoto, T.; Miyawaki, C.; Ue, H.; Yuasa, T.; Miyatsuji, A.; Moritani, T. Effects of capsaicin-containing yellow curry sauce on sympathetic nervous system activity and diet-induced thermogenesis in lean and obese young women. J. Nutr. Sci. Vitaminol. 2000, 46, 309-315. [CrossRef] [PubMed]
142. Yoneshiro, T.; Saito, M. Transient receptor potential activated brown fat thermogenesis as a target of food ingredients for obesity management. Curr. Opin. Clin. Nutr. Metab. Care 2013, 16, 625-631. [CrossRef] [PubMed]
143. Yoshioka, M.; Lim, K.; Kikuzato, S.; Kiyonaga, A.; Tanaka, H.; Shindo, M.; Suzuki, M. Effects of red-pepper diet on the energy metabolism in men. J. Nutr. Sci. Vitaminol. 1995, 41, 647-656. [CrossRef] [PubMed]
144. Kawada, T.; Watanabe, T.; Takaishi, T.; Tanaka, T.; Iwai, K. Capsaicin-induced beta-adrenergic action on energy metabolism in rats: influence of capsaicin on oxygen consumption, the respiratory quotient, and substrate utilization. Proc. Soc. Exp. Biol. Med. 1986, 183, 250-256. [CrossRef] [PubMed]
145. Baboota, R.K.; Murtaza, N.; Jagtap, S.; Singh, D.P.; Karmase, A.; Kaur, J.; Bhutani, K.K.; Boparai, R.K.; Premkumar, L.S.; Kondepudi, K.K.; et al. Capsaicin-induced transcriptional changes in hypothalamus and alterations in gut microbial count in high fat diet fed mice. J. Nutr. Biochem. 2014, 25, 893-902. [CrossRef] [PubMed]
146. Luo, Z.; Ma, L.; Zhao, Z.; He, H.; Yang, D.; Feng, X.; Ma, S.; Chen, X.; Zhu, T.; Cao, T.; et al. TRPV1 activation improves exercise endurance and energy metabolism through PGC-1alpha upregulation in mice. Cell Res. 2012, 22, 551-564. [CrossRef] [PubMed]
147. Prins, J.B.; O'Rahilly, S. Regulation of adipose cell number in man. Clin. Sci. 1997, 92, 3-11. [CrossRef] [PubMed]
148. MacDougald, O.A.; Mandrup, S. Adipogenesis: forces that tip the scales. Trends Endocrinol. Metab. 2002, 13, 5-11. [CrossRef]
149. Feng, Z.; Hai-ning, Y.; Xiao-man, C.; Zun-chen, W.; Sheng-rong, S.; Das, U.N. Effect of yellow capsicum extract on proliferation and differentiation of 3T3-L1 preadipocytes. Nutrition 2014, 30, 319-325. [CrossRef] [PubMed]
150. Hwang, J.T.; Park, I.J.; Shin, J.I.; Lee, Y.K.; Lee, S.K.; Baik, H.W.; Ha, J.; Park, O.J. Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase. Biochem. Biophys. Res. Commun. 2005, 338, 694-699. [CrossRef] [PubMed]
151. Hsu, C.L.; Yen, G.C. Effects of capsaicin on induction of apoptosis and inhibition of adipogenesis in 3T3-L1 cells. J. Agric. Food Chem. 2007, 55, 1730-1736. [CrossRef] [PubMed]
152. Ibrahim, M.; Jang, M.; Park, M.; Gobianand, K.; You, S.; Yeon, S.H.; Park, S.; Kim, M.J.; Lee, H.J. Capsaicin inhibits the adipogenic differentiation of bone marrow mesenchymal stem cells by regulating cell proliferation, apoptosis, oxidative and nitrosative stress. Food Funct. 2015, 6, 2165-2178. [CrossRef] [PubMed]
153. Browne, G.J.; Finn, S.G.; Proud, C.G. Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398. J. Biol. Chem. 2004, 279, 12220-12231. [CrossRef] [PubMed]
154. Jung, J.E.; Lee, J.; Ha, J.; Kim, S.S.; Cho, Y.H.; Baik, H.H.; Kang, I. 5-Aminoimidazole-4-carboxamideribonucleoside enhances oxidative stress-induced apoptosis through activation of nuclear factor-kappaB in mouse Neuro 2a neuroblastoma cells. Neurosci. Lett. 2004, 354, 197-200. [CrossRef] [PubMed]
155. Delzenne, N.M.; Neyrinck, A.M.; Cani, P.D. Modulation of the gut microbiota by nutrients with prebiotic properties: Consequences for host health in the context of obesity and metabolic syndrome. Microb. Cell Fact. 2011, 10 (Suppl. S1). [CrossRef] [PubMed]
156. Ley, R.E.; Backhed, F.; Turnbaugh, P.; Lozupone, C.A.; Knight, R.D.; Gordon, J.I. Obesity alters gut microbial ecology. Proc. Natl. Acad. Sci. USA 2005, 102, 11070-11075. [CrossRef] [PubMed]
157. Ley, R.E.; Turnbaugh, P.J.; Klein, S.; Gordon, J.I. Microbial ecology: human gut microbes associated with obesity. Nature 2006, 444, 1022-1023. [CrossRef] [PubMed]
158. Ouchi, N.; Parker, J.L.; Lugus, J.J.; Walsh, K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 2011, 11, 85-97. [CrossRef] [PubMed]
159. Whiting, S.; Derbyshire, E.; Tiwari, B.K. Capsaicinoids and capsinoids. A potential role for weight management? A systematic review of the evidence. Appetite 2012, 59, 341-348. [CrossRef] [PubMed]
160. Lejeune, M.P.; Kovacs, E.M.; Westerterp-Plantenga, M.S. Effect of capsaicin on substrate oxidation and weight maintenance after modest body-weight loss in human subjects. Br. J. Nutr. 2003, 90, 651-659. [CrossRef] [PubMed]
161. Oster, G.; Thompson, D.; Edelsberg, J.; Bird, A.P.; Colditz, G.A. Lifetime health and economic benefits of weight loss among obese persons. Am. J. Public Health 1999, 89, 1536-1542. [CrossRef] [PubMed]
162. Liu, W.Q.; Kanungo, A.; Toth, C. Equivalency of tricyclic antidepressants in open-label neuropathic pain study. Acta Neurol. Scand. 2014, 129, 132-141. [CrossRef] [PubMed]
163. Ahuja, K.D.; Robertson, I.K.; Geraghty, D.P.; Ball, M.J. Effects of chili consumption on postprandial glucose, insulin, and energy metabolism. Am. J. Clin. Nutr. 2006, 84, 63-69. [PubMed]
164. Chaiyasit, K.; Khovidhunkit, W.; Wittayalertpanya, S. Pharmacokinetic and the effect of capsaicin in Capsicum frutescens on decreasing plasma glucose level. J. Med. Assoc. Thail. 2009, 92, 108-113. [PubMed]
165. Yuan, L.J.; Qin, Y.; Wang, L.; Zeng, Y.; Chang, H.; Wang, J.; Wang, B.; Wan, J.; Chen, S.H.; et al. Capsaicin-containing chili improved postprandial hyperglycemia, hyperinsulinemia, and fasting lipid disorders in women with gestational diabetes mellitus and lowered the incidence of large-for-gestational-age newborns. Clin. Nutr. 2016, 35, 388-393. [CrossRef] [PubMed]
166. Tolan, I.; Ragoobirsingh, D.; Morrison, E.Y. The effect of capsaicin on blood glucose, plasma insulin levels and insulin binding in dog models. Phytother. Res. 2001, 15, 391-394. [CrossRef] [PubMed]
167. Karlsson, S.; Scheurink, A.J.; Steffens, A.B.; Ahren, B. Involvement of capsaicin-sensitive nerves in regulation of insulin secretion and glucose tolerance in conscious mice. Am. J. Physiol. 1994, 267, R1071-R1077. [PubMed]
168. Kwon, D.Y.; Kim, Y.S.; Ryu, S.Y.; Cha, M.R.; Yon, G.H.; Yang, H.J.; Kim, M.J.; Kang, S.; Park, S. Capsiate improves glucose metabolism by improving insulin sensitivity better than capsaicin in diabetic rats. J. Nutr. Biochem. 2013, 24, 1078-1085. [CrossRef] [PubMed]
169. Kang, J.H.; Kim, C.S.; Han, I.S.; Kawada, T.; Yu, R. Capsaicin, a spicy component of hot peppers, modulates adipokine gene expression and protein release from obese-mouse adipose tissues and isolated adipocytes, and suppresses the inflammatory responses of adipose tissue macrophages. FEBS Lett. 2007, 581, 4389-4396. [CrossRef] [PubMed]
170. Kang, J.H.; Goto, T.; Han, I.S.; Kawada, T.; Kim, Y.M.; Yu, R. Dietary capsaicin reduces obesity-induced insulin resistance and hepatic steatosis in obese mice fed a high-fat diet. Obesity 2010, 18, 780-787. [CrossRef] [PubMed]
171. Xu, H.; Barnes, G.T.; Yang, Q.; Tan, G.; Yang, D.; Chou, C.J.; Sole, J.; Nichols, A.; Ross, J.S.; Tartaglia, L.A.; et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Investig. 2003, 112, 1821-1830. [CrossRef] [PubMed]
172. Matsuzawa, Y.; Funahashi, T.; Kihara, S.; Shimomura, I. Adiponectin and metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 2004, 24, 29-33. [CrossRef] [PubMed]
173. Wang, P.; Yan, Z.; Zhong, J.; Chen, J.; Ni, Y.; Li, L.; Ma, L.; Zhao, Z.; Liu, D.; Zhu, Z. Transient receptor potential vanilloid 1 activation enhances gut glucagon-like peptide-1 secretion and improves glucose homeostasis. Diabetes 2012, 61, 2155-2165. [CrossRef] [PubMed]
174. + sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell 2006, 127, 1123-1135. [CrossRef] [PubMed]
175. Gram, D.X.; Ahren, B.; Nagy, I.; Olsen, U.B.; Brand, C.L.; Sundler, F.; Tabanera, R.; Svendsen, O.; Carr, R.D.; Santha, P.; et al. Capsaicin-sensitive sensory fibers in the islets of Langerhans contribute to defective insulin secretion in Zucker diabetic rat, an animal model for some aspects of human type 2 diabetes. Eur. J. Neurosci. 2007, 25, 213-223. [CrossRef] [PubMed]
176. Akiba, Y.; Kato, S.; Katsube, K.; Nakamura, M.; Takeuchi, K.; Ishii, H.; Hibi, T. Transient receptor potential vanilloid subfamily 1 expressed in pancreatic islet beta cells modulates insulin secretion in rats. Biochem. Biophys. Res. Commun. 2004, 321, 219-225. [CrossRef] [PubMed]
177. Nevius, E.; Srivastava, P.K.; Basu, S. Oral ingestion of Capsaicin, the pungent component of chili pepper, enhances a discreet population of macrophages and confers protection from autoimmune diabetes. Mucosal. Immunol. 2012, 5, 76-86. [CrossRef] [PubMed]
178. Harada, N.; Okajima, K. Effects of capsaicin and isoflavone on blood pressure and serumlevels of insulin-like growth factor-I in normotensive and hypertensive volunteers with alopecia. Biosci. Biotechnol. Biochem. 2009, 73, 1456-1459. [CrossRef] [PubMed]
179. Li, J.; Wang, D.H. Function and regulation of the vanilloid receptor in rats fed a high salt diet. J. Hypertens. 2003, 21, 1525-1530. [CrossRef] [PubMed]
180. Peng, J.; Li, Y.J. The vanilloid receptor TRPV1: role in cardiovascular and gastrointestinal protection. Eur. J. Pharmacol. 2010, 627, 1-7. [CrossRef] [PubMed]
181. Zvara, A.; Bencsik, P.; Fodor, G.; Csont, T.; Hackler, L., Jr.; Dux, M.; Furst, S.; Jancso, G.; Puskas, L.G.; Ferdinandy, P. Capsaicin-sensitive sensory neurons regulate myocardial function and gene expression pattern of rat hearts: A DNA microarray study. FASEB J. 2006, 20, 160-162. [CrossRef] [PubMed]
182. Deng, P.Y.; Li, Y.J. Calcitonin gene-related peptide and hypertension. Peptides 2005, 26, 1676-1685. [CrossRef] [PubMed]
183. Chai, W.; Mehrotra, S.; Jan Danser, A.H.; Schoemaker, R.G. The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning in isolated rat hearts. Eur. J. Pharmacol. 2006, 531, 246-253. [CrossRef] [PubMed]
184. Li, Y.J.; Peng, J. The cardioprotection of calcitonin gene-related peptide-mediated preconditioning. Eur. J. Pharmacol. 2002, 442, 173-177. [CrossRef]
185. Zhou, F.W.; Li, Y.J.; Deng, H.W. Early and delayed protection by capsaicin against reperfusion injury in rat hearts. Zhongguo Yao Li Xue Bao 1999, 20, 912-916. [PubMed]
186. Peng, J.; Lu, R.; Deng, H.W.; Li, Y.J. Involvement of alpha-calcitonin gene-related peptide in monophosphoryl lipid A-induced delayed preconditioning in rat hearts. Eur. J. Pharmacol. 2002, 436, 89-96. [CrossRef]
187. Peng, J.; Lu, R.; Xiao, L.; Deng, H.W.; Li, Y.J. Involvement of alpha-calcitonin gene-related peptide in heat stress-induced delayed preconditioning in rat hearts. Clin. Exp. Pharmacol. Physiol. 2002, 29, 569-574. [CrossRef] [PubMed]
188. Wang, D.H. Transient receptor potential vanilloid channels in hypertension, inflammation, and end organ damage: an imminent target of therapy for cardiovascular disease? Curr. Opin. Cardiol. 2008, 23, 356-363. [CrossRef] [PubMed]
189. Xu, X.; Wang, P.; Zhao, Z.; Cao, T.; He, H.; Luo, Z.; Zhong, J.; Gao, F.; Zhu, Z.; Li, L.; et al. Activation of transient receptor potential vanilloid 1 by dietary capsaicin delays the onset of stroke in stroke-prone spontaneously hypertensive rats. Stroke 2011, 42, 3245-3451. [CrossRef] [PubMed]
190. Yang, D.; Luo, Z.; Ma, S.; Wong, W.T.; Ma, L.; Zhong, J.; He, H.; Zhao, Z.; Cao, T.; Yan, Z.; et al. Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension. Cell Metab. 2010, 12, 130-141. [CrossRef] [PubMed]
191. Bigal, M.E.; Walter, S.; Rapoport, A.M. Calcitonin gene-related peptide (CGRP) and migraine current understanding and state of development. Headache 2013, 53, 1230-1244. [CrossRef] [PubMed]
192. Ma, L.; Zhong, J.; Zhao, Z.; Luo, Z.; Ma, S.; Sun, J.; He, H.; Zhu, T.; Liu, D.; Zhu, Z.; et al. Activation of TRPV1 reduces vascular lipid accumulation and attenuates atherosclerosis. Cardiovasc. Res. 2011, 92, 504-513. [CrossRef] [PubMed]
193. Li, B.H.; Yin, Y.W.; Liu, Y.; Pi, Y.; Guo, L.; Cao, X.J.; Gao, C.Y.; Zhang, L.L.; Li, J.C. TRPV1 activation impedes foam cell formation by inducing autophagy in oxLDL-treated vascular smooth muscle cells. Cell Death. Dis. 2014, 5. [CrossRef] [PubMed]
194. Stocker, R.; Keaney, J.F., Jr. Role of oxidative modifications in atherosclerosis. Physiol. Rev. 2004, 84, 1381-1478. [CrossRef] [PubMed]
195. Ahuja, K.D.; Kunde, D.A.; Ball, M.J.; Geraghty, D.P. Effects of capsaicin, dihydrocapsaicin, and curcumin on copper-induced oxidation of human serum lipids. J. Agric. Food Chem. 2006, 54, 6436-6439. [CrossRef] [PubMed]
196. Manjunatha, H.; Srinivasan, K. Protective effect of dietary curcumin and capsaicin on induced oxidation of low-density lipoprotein, iron-induced hepatotoxicity and carrageenan-induced inflammation in experimental rats. FEBS J. 2006, 273, 4528-4537. [CrossRef] [PubMed]
197. Manjunatha, H.; Srinivasan, K. Hypolipidemic and antioxidant effects of dietary curcumin and capsaicin in induced hypercholesterolemic rats. Lipids 2007, 42, 1133-1142. [CrossRef] [PubMed]
198. Ahuja, K.D.; Ball, M.J. Effects of daily ingestion of chilli on serum lipoprotein oxidation in adult men and women. Br. J. Nutr. 2006, 96, 239-242. [CrossRef] [PubMed]
199. Adams, M.J.; Ahuja, K.D.; Geraghty, D.P. Effect of capsaicin and dihydrocapsaicin on in vitro blood coagulation and platelet aggregation. Thromb. Res. 2009, 124, 721-723. [CrossRef] [PubMed]
200. Mittelstadt, S.W.; Nelson, R.A.; Daanen, J.F.; King, A.J.; Kort, M.E.; Kym, P.R.; Lubbers, N.L.; Cox, B.F.; Lynch, J.J., 3rd. Capsaicin-induced inhibition of platelet aggregation is not mediated by transient receptor potential vanilloid type 1. Blood Coagul. Fibrinolysis 2012, 23, 94-97. [CrossRef] [PubMed]
201. Bhatt, D.L.; Topol, E.J. Scientific and therapeutic advances in antiplatelet therapy. Nat. Rev. Drug Discov. 2003, 2, 15-28. [CrossRef] [PubMed]
202. Aranda, F.J.; Villalain, J.; Gomez-Fernandez, J.C. Capsaicin affects the structure and phase organization of phospholipid membranes. Biochim. Biophys. Acta 1995, 1234, 225-234. [CrossRef]
203. Meddings, J.B.; Hogaboam, C.M.; Tran, K.; Reynolds, J.D.; Wallace, J.L. Capsaicin effects on non-neuronal plasma membranes. Biochim. Biophys. Acta 1991, 1070, 43-50. [CrossRef]
204. Harper, A.G.; Brownlow, S.L.; Sage, S.O. A role for TRPV1 in agonist-evoked activation of human platelets. J. Thromb. Haemost 2009, 7, 330-338. [CrossRef] [PubMed]
205. Poston, G.J. Global cancer surgery: The Lancet Oncology review. Eur. J. Surg. Oncol. 2015, 41, 1559-1561. [CrossRef] [PubMed]
206. Amantini, C.; Ballarini, P.; Caprodossi, S.; Nabissi, M.; Morelli, M.B.; Lucciarini, R.; Cardarelli, M.A.; Mammana, G.; Santoni, G. Triggering of transient receptor potential vanilloid type 1 (TRPV1) by capsaicin induces Fas/CD95-mediated apoptosis of urothelial cancer cells in an ATM-dependent manner. Carcinogenesis 2009, 30, 1320-1329. [CrossRef] [PubMed]
207. Zhang, R.; Humphreys, I.; Sahu, R.P.; Shi, Y.; Srivastava, S.K. In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ROS generation and mitochondrial death pathway. Apoptosis 2008, 13, 1465-1478. [CrossRef] [PubMed]
208. Lu, H.F.; Chen, Y.L.; Yang, J.S.; Yang, Y.Y.; Liu, J.Y.; Hsu, S.C.; Lai, K.C.; Chung, J.G. Antitumor activity of capsaicin on human colon cancer cells in vitro and colo 205 tumor xenografts in vivo. J. Agric. Food Chem. 2010, 58, 12999-3005. [CrossRef] [PubMed]
209. Surh, Y.J.; Lee, S.S. Capsaicin in hot chili pepper: Carcinogen, co-carcinogen or anticarcinogen? Food Chem. Toxicol. 1996, 34, 313-316. [CrossRef]
210. Chen, D.; Yang, Z.; Wang, Y.; Zhu, G.; Wang, X. Capsaicin induces cycle arrest by inhibiting cyclin-dependent-kinase in bladder carcinoma cells. Int. J. Urol. 2012, 19, 662-668. [CrossRef] [PubMed]
211. Zheng, L.; Chen, J.; Ma, Z.; Liu, W.; Yang, F.; Yang, Z.; Wang, K.; Wang, X.; He, D.; Li, L. Capsaicin causes inactivation and degradation of the androgen receptor by inducing the restoration of miR-449a in prostate cancer. Oncol. Rep. 2015, 34, 1027-1034. [CrossRef] [PubMed]
212. Baig, S.; Seevasant, I.; Mohamad, J.; Mukheem, A.; Huri, H.Z.; Kamarul, T. Potential of apoptotic pathway-targeted cancer therapeutic research: Where do we stand? Cell Death Dis. 2016, 7. [CrossRef] [PubMed]
213. Clark, R.; Lee, S.H. Anticancer Properties of Capsaicin against Human Cancer. Anticancer Res. 2016, 36, 837-843. [PubMed]
214. Bley, K.; Boorman, G.; Mohammad, B.; McKenzie, D.; Babbar, S. A comprehensive review of the carcinogenic and anticarcinogenic potential of capsaicin. Toxicol. Pathol. 2012, 40, 847-873. [CrossRef] [PubMed]
215. Watjen, W.; Weber, N.; Lou, Y.J.; Wang, Z.Q.; Chovolou, Y.; Kampkotter, A.; Kahl, R.; Proksch, P. Prenylation enhances cytotoxicity of apigenin and liquiritigenin in rat H4IIE hepatoma and C6 glioma cells. Food Chem. Toxicol. 2007, 45, 119-124. [CrossRef] [PubMed]
216. Chow, J.; Norng, M.; Zhang, J.; Chai, J. TRPV6 mediates capsaicin-induced apoptosis in gastric cancer cells-Mechanisms behind a possible new "hot" cancer treatment. Biochim. Biophys. Acta 2007, 1773, 565-576. [CrossRef] [PubMed]
217. 2+-mediated mitochondrial damage and cytochrome c release. J. Immunol. 2006, 177, 4322-4329. [CrossRef] [PubMed]
218. Kastan, M.B.; Bartek, J. Cell-cycle checkpoints and cancer. Nature 2004, 432, 316-323. [CrossRef] [PubMed]
219. Lee, S.H.; Richardson, R.L.; Dashwood, R.H.; Baek, S.J. Capsaicin represses transcriptional activity of beta-catenin in human colorectal cancer cells. J. Nutr. Biochem. 2012, 23, 646-655. [CrossRef] [PubMed]
220. Thoennissen, N.H.; O'Kelly, J.; Lu, D.; Iwanski, G.B.; La, D.T.; Abbassi, S.; Leiter, A.; Karlan, B.; Mehta, R.; Koeffler, H.P. Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway. Oncogene 2010, 29, 285-296. [CrossRef] [PubMed]
221. Min, J.K.; Han, K.Y.; Kim, E.C.; Kim, Y.M.; Lee, S.W.; Kim, O.H.; Kim, K.W.; Gho, Y.S.; Kwon, Y.G. Capsaicin inhibits in vitro and in vivo angiogenesis. Cancer Res. 2004, 64, 644-651. [CrossRef] [PubMed]
222. Chakraborty, S.; Adhikary, A.; Mazumdar, M.; Mukherjee, S.; Bhattacharjee, P.; Guha, D.; Choudhuri, T.; Chattopadhyay, S.; Sa, G.; Sen, A.; et al. Capsaicin-induced activation of p53-SMAR1 auto-regulatory loop down-regulates VEGF in non-small cell lung cancer to restrain angiogenesis. PLoS ONE 2014, 9. [CrossRef] [PubMed]
223. Bode, A.M.; Dong, Z. The two faces of capsaicin. Cancer Res. 2011, 71, 2809-2814. [CrossRef] [PubMed]
224. Hoch-Ligeti, C. Production of liver tumours by dietary means; effect of feeding chilies [Capsicum frutescens and annuum (Linn.)] to rats. Acta Unio Int. Contra Cancrum. 1951, 7, 606-611.
225. Toth, B.; Gannett, P. Carcinogenicity of lifelong administration of capsaicin of hot pepper in mice. In Vivo 1992, 6, 59-63. [PubMed]
226. Liu, Z.; Zhu, P.; Tao, Y.; Shen, C.; Wang, S.; Zhao, L.; Wu, H.; Fan, F.; Lin, C.; Chen, C.; et al. Cancer-promoting effect of capsaicin on DMBA/TPA-induced skin tumorigenesis by modulating inflammation, Erk and p38 in mice. Food Chem. Toxicol. 2015, 81, 1-8. [CrossRef] [PubMed]
227. Agrawal, R.C.; Wiessler, M.; Hecker, E.; Bhide, S.V. Tumour-promoting effect of chilli extract in BALB/c mice. Int. J. Cancer 1986, 38, 689-695. [CrossRef] [PubMed]
228. Kim, J.P.; Park, J.G.; Lee, M.D.; Han, M.D.; Park, S.T.; Lee, B.H.; Jung, S.E. Co-carcinogenic effects of several Korean foods on gastric cancer induced by N-methyl-N′-nitro-N-nitrosoguanidine in rats. Jpn. J. Surg. 1985, 15, 427-437. [CrossRef] [PubMed]
229. Erin, N.; Boyer, P.J.; Bonneau, R.H.; Clawson, G.A.; Welch, D.R. Capsaicin-mediated denervation of sensory neurons promotes mammary tumor metastasis to lung and heart. Anticancer Res. 2004, 24, 1003-1009. [PubMed]
230. Serra, I.; Yamamoto, M.; Calvo, A.; Cavada, G.; Baez, S.; Endoh, K.; Watanabe, H.; Tajima, K. Association of chili pepper consumption, low socioeconomic status and longstanding gallstones with gallbladder cancer in a Chilean population. Int. J. Cancer 2002, 102, 407-411. [CrossRef] [PubMed]
231. Lopez-Carrillo, L.; Hernandez Avila, M.; Dubrow, R. Chili pepper consumption and gastric cancer in Mexico: a case-control study. Am. J. Epidemiol. 1994, 139, 263-271. [PubMed]
232. Talbot, S.; Abdulnour, R.E.; Burkett, P.R.; Lee, S.; Cronin, S.J.; Pascal, M.A.; Laedermann, C.; Foster, S.L.; Tran, J.V.; Lai, N.; et al. Silencing Nociceptor Neurons Reduces Allergic Airway Inflammation. Neuron 2015, 87, 341-354. [CrossRef] [PubMed]
233. Rehman, R.; Bhat, Y.A.; Panda, L.; Mabalirajan, U. TRPV1 inhibition attenuates IL-13 mediated asthma features in mice by reducing airway epithelial injury. Int. Immunopharmacol. 2013, 15, 597-605. [CrossRef] [PubMed]
234. George, L.; Brightling, C.E. Eosinophilic airway inflammation: Role in asthma and chronic obstructive pulmonary disease. Ther. Adv. Chronic Dis. 2016, 7, 34-51. [CrossRef] [PubMed]
235. Chiu, I.M.; Heesters, B.A.; Ghasemlou, N.; Von Hehn, C.A.; Zhao, F.; Tran, J.; Wainger, B.; Strominger, A.; Muralidharan, S.; Horswill, A.R.; et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 2013, 501, 52-57. [CrossRef] [PubMed]
236. Chiu, I.M.; von Hehn, C.A.; Woolf, C.J. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat. Neurosci. 2012, 15, 1063-1067. [CrossRef] [PubMed]
237. Settipane, R.A.; Lieberman, P. Update on nonallergic rhinitis. Ann. Allergy Asthma Immunol. 2001, 86, 494-507; quiz 507-508. [CrossRef]
238. Stjärne, P.; Lundblad, L.; Änggard, A.; Lunderberg, J.M. Local capsaicin treatment of the nasal mucosa reduces symptoms in patients with nonallergic nasal hyperreactivity. Am. J. Rhinol. 1991, 5, 145-151. [CrossRef]
239. Van Rijswijk, J.B.; Boeke, E.L.; Keizer, J.M.; Mulder, P.G.; Blom, H.M.; Fokkens, W.J. Intranasal capsaicin reduces nasal hyperreactivity in idiopathic rhinitis: A double-blind randomized application regimen study. Allergy 2003, 58, 754-761. [CrossRef] [PubMed]
240. Blom, H.M.; Van Rijswijk, J.B.; Garrelds, I.M.; Mulder, P.G.; Timmermans, T.; Gerth vanWijk, R. Intranasal capsaicin is efficacious in non-allergic, non-infectious perennial rhinitis. A placebo-controlled study. Clin. Exp. Allergy 1997, 27, 796-801. [CrossRef] [PubMed]
241. Gerth Van Wijk, R.; Terreehorst, I.T.; Mulder, P.G.; Garrelds, I.M.; Blom, H.M.; Popering, S. Intranasal capsaicin is lacking therapeutic effect in perennial allergic rhinitis to house dust mite. A placebo-controlled study. Clin. Exp. Allergy 2000, 30, 1792-1798. [CrossRef] [PubMed]
242. Van Gerven, L.; Alpizar, Y.A.; Wouters, M.M.; Hox, V.; Hauben, E.; Jorissen, M.; Boeckxstaens, G.; Talavera, K.; Hellings, P.W. Capsaicin treatment reduces nasal hyperreactivity and transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) overexpression in patients with idiopathic rhinitis. J. Allergy Clin. Immunol. 2014, 133, 1332-1339. e3. [CrossRef] [PubMed]
243. Liu, T.; Ji, R.R. New insights into the mechanisms of itch: Are pain and itch controlled by distinct mechanisms? Pflugers Arch. 2013, 465, 1671-1685. [CrossRef] [PubMed]
244. Chiu, I.M.; Barrett, L.B.; Williams, E.K.; Strochlic, D.E.; Lee, S.; Weyer, A.D.; Lou, S.; Bryman, G.S.; Roberson, D.P.; Ghasemlou, N.; et al. Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity. Elife 2014, 3. [CrossRef] [PubMed]
245. Roberson, D.P.; Gudes, S.; Sprague, J.M.; Patoski, H.A.; Robson, V.K.; Blasl, F.; Duan, B.; Oh, S.B.; Bean, B.P.; Ma, Q.; et al. Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons. Nat. Neurosci. 2013, 16, 910-918. [CrossRef] [PubMed]
246. Riol-Blanco, L.; Ordovas-Montanes, J.; Perro, M.; Naval, E.; Thiriot, A.; Alvarez, D.; Paust, S.; Wood, J.N.; von Andrian, U.H. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 2014, 510, 157-161. [CrossRef] [PubMed]
247. Ellis, C.N.; Berberian, B.; Sulica, V.I.; Dodd, W.A.; Jarratt, M.T.; Katz, H.I.; Prawer, S.; Krueger, G.; Rex, I.H., Jr.; Wolf, J.E. A double-blind evaluation of topical capsaicin in pruritic psoriasis. J. Am. Acad. Dermatol. 1993, 29, 438-442. [CrossRef]
248. Bernstein, J.E.; Parish, L.C.; Rapaport, M.; Rosenbaum, M.M.; Roenigk, H.H., Jr. Effects of topically applied capsaicin on moderate and severe psoriasis vulgaris. J. Am. Acad. Dermatol. 1986, 15, 504-507. [CrossRef]
249. Andersen, H.H.; Sand, C.; Elberling, J. Considerable Variability in the Efficacy of 8% Capsaicin Topical Patches in the Treatment of Chronic Pruritus in 3 Patients with Notalgia Paresthetica. Ann. Dermatol. 2016, 28, 86-89. [CrossRef] [PubMed]
250. Misery, L.; Erfan, N.; Castela, E.; Brenaut, E.; Lanteri-Minet, M.; Lacour, J.P.; Passeron, T. Successful treatment of refractory neuropathic pruritus with capsaicin 8% patch: A bicentric retrospective study with long-term follow-up. Acta Derm. Venereol. 2015, 95, 864-865. [CrossRef] [PubMed]
251. Holzer, P.; Pabst, M.A. Visceral Afferent Neurons: Role in Gastric Mucosal Protection. News Physiol. Sci. 1999, 14, 201-206. [PubMed]
252. Holzer, P.; Sametz, W. Gastric mucosal protection against ulcerogenic factors in the rat mediated by capsaicin-sensitive afferent neurons. Gastroenterology 1986, 91, 975-981. [CrossRef]
253. Takeuchi, K.; Niida, H.; Matsumoto, J.; Ueshima, K.; Okabe, S. Gastric motility changes in capsaicin-induced cytoprotection in the rat stomach. Jpn. J. Pharmacol. 1991, 55, 147-155. [CrossRef] [PubMed]
254. Sobue, M.; Joh, T.; Oshima, T.; Suzuki, H.; Seno, K.; Kasugai, K.; Nomura, T.; Ohara, H.; Yokoyama, Y.; Itoh, M. Contribution of capsaicin-sensitive afferent nerves to rapid recovery from ethanol-induced gastric epithelial damage in rats. J. Gastroenterol. Hepatol. 2003, 18, 1188-1195. [CrossRef] [PubMed]
255. Mozsik, G.; Szolcsanyi, J.; Racz, I. Gastroprotection induced by capsaicin in healthy human subjects. World J. Gastroenterol. 2005, 11, 5180-5184. [PubMed]
256. Fukushima, K.; Aoi, Y.; Kato, S.; Takeuchi, K. Gastro-protective action of lafutidine mediated by capsaicin-sensitive afferent neurons without interaction with TRPV1 and involvement of endogenous prostaglandins. World J. Gastroenterol. 2006, 12, 3031-3017. [CrossRef] [PubMed]
257. Satyanarayana, M.N. Capsaicin and gastric ulcers. Crit. Rev. Food Sci. Nutr. 2006, 46, 275-328. [CrossRef] [PubMed]
258. Lee, I.O.; Lee, K.H.; Pyo, J.H.; Kim, J.H.; Choi, Y.J.; Lee, Y.C. Anti-inflammatory effect of capsaicin in Helicobacter pylori-infected gastric epithelial cells. Helicobacter 2007, 12, 510-517. [CrossRef] [PubMed]
259. Jones, N.L.; Shabib, S.; Sherman, P.M. Capsaicin as an inhibitor of the growth of the gastric pathogen Helicobacter pylori. FEMS Microbiol. Lett. 1997, 146, 223-227. [CrossRef] [PubMed]
260. 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 1995, 36, 664-669. [CrossRef] [PubMed]
261. Mhaskar, R.S.; Ricardo, I.; Azliyati, A.; Laxminarayan, R.; Amol, B.; Santosh, W.; Boo, K. Assessment of risk factors of helicobacter pylori infection and peptic ulcer disease. J. Glob. Infect. Dis. 2013, 5, 60-67. [CrossRef] [PubMed]
262. Foster, H.E.; Lake, A.G. Use of Vanilloids in Urologic Disorders. In Capsaicin as a Therapeutic Molecule; Abdel-Salam, E.O.M., Ed.; Springer Basel: Basel, Switzerland, 2014; pp. 307-317.
263. Haab, F. Chapter 1: The conditions of neurogenic detrusor overactivity and overactive bladder. Neurourol. Urodyn. 2014, 33 (Suppl. S3), S2-S5. [CrossRef] [PubMed]
264. Wouters, A.T.; Casagrande, R.A.; Wouters, F.; Watanabe, T.T.; Boabaid, F.M.; Cruz, C.E.; Driemeier, D. An outbreak of aflatoxin poisoning in dogs associated with aflatoxin B1-contaminated maize products. J. Vet. Diagn. Investig. 2013, 25, 282-287. [CrossRef] [PubMed]
265. Wadie, B.S. Management of refractory OAB in the non-neurogenic patient. Curr. Urol. Rep. 2014, 15, 438. [CrossRef] [PubMed]
266. Yamaguchi, O.; Nishizawa, O.; Takeda, M.; Yokoyama, O.; Homma, Y.; Kakizaki, H.; Obara, K.; Gotoh, M.; Igawa, Y.; Seki, N.; et al. Clinical guidelines for overactive bladder. Int. J. Urol. 2009, 16, 126-142. [CrossRef] [PubMed]
267. De Seze, M.; Wiart, L.; Joseph, P.A.; Dosque, J.P.; Mazaux, J.M.; Barat, M. Capsaicin and neurogenic detrusor hyperreflexia: A double-blind placebo-controlled study in 20 patients with spinal cord lesions. Neurourol. Urodyn. 1998, 17, 513-523. [CrossRef]
268. Wiart, L.; Joseph, P.A.; Petit, H.; Dosque, J.P.; de Seze, M.; Brochet, B.; Deminiere, C.; Ferriere, J.M.; Mazaux, J.M.; N'Guyen, P.; et al. The effects of capsaicin on the neurogenic hyperreflexic detrusor. A double blind placebo controlled study in patients with spinal cord disease. Preliminary results. Spinal Cord 1998, 36, 95-99. [CrossRef] [PubMed]
269. George, J.; Tharion, G.; Richar, J.; Macaden, A.S.; Thomas, R.; Bhattacharji, S. The effectiveness of intravesical oxybutynin, propantheline, and capsaicin in the management of neuropathic bladder following spinal cord injury. Sci. World J. 2007, 7, 1683-1690. [CrossRef] [PubMed]
270. Soontrapa, S.; Ruksakul, W.; Nonthasood, B.; Tappayuthpijarn, P. The efficacy of Thai capsaicin in management of overactive bladder and hypersensitive bladder. J. Med. Assoc. Thail. 2003, 86, 861-867. [PubMed]
271. MacDonald, R.; Monga, M.; Fink, H.A.; Wilt, T.J. Neurotoxin treatments for urinary incontinence in subjects with spinal cord injury or multiple sclerosis: A systematic review of effectiveness and adverse effects. J. Spinal Cord Med. 2008, 31, 157-165. [PubMed]
272. De Seze, M.; Gallien, P.; Denys, P.; Labat, J.J.; Serment, G.; Grise, P.; Salle, J.Y.; Blazejewski, S.; Hazane, C.; Moore, N.; et al. Intravesical glucidic capsaicin versus glucidic solvent in neurogenic detrusor overactivity: A double blind controlled randomized study. Neurourol. Urodyn. 2006, 25, 752-757. [CrossRef] [PubMed]
273. Thomas, C.; Kim, J.H.; Torimoto, K.; Kwon, D.D.; Kim, Y.T.; Tyagi, P.; Yoshimura, N.; Chancellor, M.B. Early capsaicin intervention for neurogenic bladder in a rat model of spinal cord injury. Biomed. Res. 2007, 28, 255-259. [CrossRef] [PubMed]
274. Everaerts, W.; Gevaert, T.; Nilius, B.; De Ridder, D. On the origin of bladder sensing: Trips in urology. Neurourol. Urodyn. 2008, 27, 264-273. [CrossRef] [PubMed]
275. Apostolidis, A.; Brady, C.M.; Yiangou, Y.; Davis, J.; Fowler, C.J.; Anand, P. Capsaicin receptor TRPV1 in urothelium of neurogenic human bladders and effect of intravesical resiniferatoxin. Urology 2005, 65, 400-405. [CrossRef] [PubMed]
276. Li, M.; Sun, Y.; Simard, J.M.; Chai, T.C. Increased transient receptor potential vanilloid type 1 (TRPV1) signaling in idiopathic overactive bladder urothelial cells. Neurourol. Urodyn. 2011, 30, 606-611. [CrossRef] [PubMed]
277. Birder, L.A.; Wolf-Johnston, A.S.; Sun, Y.; Chai, T.C. Alteration in TRPV1 and Muscarinic (M3) receptor expression and function in idiopathic overactive bladder urothelial cells. Acta Physiol. 2013, 207, 123-129. [CrossRef] [PubMed]
278. Anand, P.; Bley, K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br. J. Anaesth. 2011, 107, 490-502. [CrossRef] [PubMed]
279. Derry, S.; Lloyd, R.; Moore, R.A.; McQuay, H.J. Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database Syst. Rev. 2009, CD007393. [CrossRef]
280. Hempenstall, K.; Nurmikko, T.J.; Johnson, R.W.; A'Hern, R.P.; Rice, A.S. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med. 2005, 2, e164. [CrossRef] [PubMed]
281. McCormack, P.L. Capsaicin dermal patch: In non-diabetic peripheral neuropathic pain. Drugs 2010, 70, 1831-1842. [CrossRef] [PubMed]
282. Simpson, D.M.; Brown, S.; Tobias, J.K.; Vanhove, G.F.; Group, N.-C.S. NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy: Results of a 52-week open-label study. Clin. J. Pain 2014, 30, 134-142. [CrossRef] [PubMed]
283. Mankowski, C.; Patel, S.; Trueman, D.; Bentley, A.; Poole, C. Cost-Effectiveness of Capsaicin 8% Patch Compared with Pregabalin for the Treatment of Patients with Peripheral Neuropathic Pain in Scotland. PLoS ONE 2016, 11. [CrossRef] [PubMed]
284. Haanpaa, M.; Cruccu, G.; Nurmikko, T.J.; McBride, W.T.; Docu Axelarad, A.; Bosilkov, A.; Chambers, C.; Ernault, E.; Abdulahad, A.K. Capsaicin 8% patch versus oral pregabalin in patients with peripheral neuropathic pain. Eur. J. Pain 2016, 20, 316-328. [CrossRef] [PubMed]
285. Shin, K.O.; Moritani, T. Alterations of autonomic nervous activity and energy metabolism by capsaicin ingestion during aerobic exercise in healthy men. J. Nutr. Sci. Vitaminol. 2007, 53, 124-132. [CrossRef] [PubMed]
286. Bernstein, J.A.; Davis, B.P.; Picard, J.K.; Cooper, J.P.; Zheng, S.; Levin, L.S. A randomized, double-blind, parallel trial comparing capsaicin nasal spray with placebo in subjects with a significant component of nonallergic rhinitis. Ann. Allergy Asthma Immunol. 2011, 107, 171-178. [CrossRef] [PubMed]
287. Ciabatti, P.G.; D'Ascanio, L. Intranasal Capsicum spray in idiopathic rhinitis: a randomized prospective application regimen trial. Acta Otolaryngol. 2009, 129, 367-371. [CrossRef] [PubMed]