13. Szallasi A, Blumberg PM (1999) Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 51: 159–212. 14. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, et al. (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389: 816–824. 15. Trevisani M, Smart D, Gunthorpe MJ, Tognetto M, Barbieri M, et al. (2002) Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat Neurosci 5: 546–551. 16. Ugawa S, Ueda T, Ishida Y, Nishigaki M, Shimada S (2002) Amiloride- blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. J Clin Invest 110: 1185–1190. 17. Shinoda M, Ogino A, Ozaki N, Urano H, Hironaka K, et al. (2008) Involvement of TRPV1 in nociceptive behavior in a rat model of cancer pain. J Pain 9: 687–699. 18. Hartel M, di Mola FF, Selvaggi F, Mascetta G, Wente MN, et al. (2006) Vanilloids in pancreatic cancer: potential for chemotherapy and pain management. Gut 55: 519–528. 19. Lazzeri M, Vannucchi MG, Spinelli M, Bizzoco E, Beneforti P, et al. (2005) Transient receptor potential vanilloid type 1 (TRPV1) expression changes from normal urothelium to transitional cell carcinoma of human bladder. Eur Urol 48: 691–698. 20. Gopinath P, Wan E, Holdcroft A, Facer P, Davis JB, et al. (2005) Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain. BMC Womens Health 5: 2. 21. Heck H, Casanova M (2004) The implausibility of leukemia induction by formaldehyde: a critical review of the biological evidence on distant-site toxicity. Regul Toxicol Pharmacol 40: 92–106. 22. Ray M, Mediratta PK, Mahajan P, Sharma KK (2004) Evaluation of the role of melatonin in formalin-induced pain response in mice. Indian J Med Sci 58: 122–130. 23. Petrus M, Peier AM, Bandell M, Hwang SW, Huynh T, et al. (2007) A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. Mol Pain 3: 40. 24. Trezl L, Rusznak I, Tyihak E, Szarvas T, Szende B (1983) Spontaneous N epsilon-methylation and N epsilon-formylation reactions between L-lysine and formaldehyde inhibited by L-ascorbic acid. Biochem J 214: 289–292. 25. Shi Y, Lan F, Matson C, Mulliga P, Whetstine JR, et al. (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119: 941–953. 26. Wang Y, Zhang H, Chen Y, Sun Y, Yang F, et al. (2009) LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 138: 660–762. 27. Lizcano JM, Escrich E, Ribalta T, Muntane J, Unzeta M (1991) Amine oxidase activities in rat breast cancer induced experimentally with 7,12-dimethylben- z(alpha)anthracene. Biochem Pharmacol 42: 263–269. 28. Yu PH, Lai CT, Zuo DM (1997) Formation of formaldehyde from adrenaline in vivo: a potential risk factor for stress-related angiopathy. Neurochem Res 22: 615–620. 29. Choi JY, Abel J, Neuhaus T, Ko Y, Harth V, et al. (2003) Role of alcohol and genetic polymorphisms of CYP2E1 and ALDH2 in breast cancer development. Pharmacogenetics 13: 67–72. 30. Retfalvi T, Nemeth ZI, Sarudi I, Albert L (1998) Alteration of endogenous formaldehyde level following mercury accumulation in different pig tissues. Acta Biol Hung 49: 375–379. 31. Terry MB, Gammon MD, Zhang FF, Knight JA, Wang Q, et al. (2006) ADH3 genotype, alcohol intake and breast cancer risk. Carcinogenesis 27: 840–847. 32. Teng S, Beard K, Pourahmad J, Moridani M, Easson E, et al. (2001) The formaldehyde metabolic detoxification enzyme systems and molecular cytotoxic mechanism in isolated rat hepatocytes. Chem Biol Interact 130-132: 285–296. 33. Hedberg JJ, Hoog JO, Nilsson JA, Xi Z, Elfwing A, et al. (2000) Expression of alcohol dehydrogenase 3 in tissue and cultured cells from human oral mucosa. Am J Pathol 157: 1745–1755. 34. Gronvall JL, Garpenstrand H, Oreland L, Ekblom J (1998) Autoradiographic imaging of formaldehyde adducts in mice: possible relevance for vascular damage in diabetes. Life Sci 63: 759–768. 35. Wang M, Cheng G, Balbo S, Carmella SG, Villalta PW, et al. (2009) Clear differences in levels of a formaldehyde-DNA adduct in leukocytes of smokers and nonsmokers. Cancer Res 69: 7170–7174. 36. Nagae M, Hiraga T, Yoneda T (2007) Acidic microenvironment created by osteoclasts causes bone pain associated with tumor colonization. J Bone Miner Metab 25: 99–104. 37. Griffiths JR (1991) Are cancer cells acidic? Br J Cancer 64: 425–427. 38. Reeh PW, Steen KH (1996) Tissue acidosis in nociception and pain. Prog Brain Res 113: 143–151. 39. Tortorici S, Burruano F, Difalco P (2007) Maxillary bone necrosis following the use of formaldehyde containing paste: management and case series. Br Dent J 203: 511–512. 40. Rozylo TK, Siembida R, Nemeth ZI, Albert L, Tyihak E (2000) HPLC-OPLC- MS investigation of change of formaldehyde and its generators in human teeth of different physiological stage. Biomed Chromatogr 14: 173–179. 41. Ho YC, Huang FM, Chang YC (2007) Cytotoxicity of formaldehyde on human osteoblastic cells is related to intracellular glutathione levels. J Biomed Mater Res B Appl Biomate 83: 340–344. Formaldehyde and Cancer Pain 42. Huang FM, Chou LS, Chou MY, Chang YC (2005) Protective effect of NAC on formaldehyde-containing-ZOE-based root-canal-sealers-induced cyclooxygen- ase-2 expression and cytotoxicity in human osteoblastic cells. J Biomed Mater Res B Appl Biomater 74: 768–773. 43. Walker K, Medhurst SJ, Kidd BL, Glatt M, Bowes M, et al. (2002) Disease modifying and anti-nociceptive effects of the bisphosphonate, zoledronic acid in a model of bone cancer pain. Pain 100: 219–229. 44. Medhurst SJ, Walker K, Bowes M, Kidd BL, Glatt M, et al. (2002) A rat model of bone cancer pain. Pain 96: 129–140. 45. Kanai Y, Hara T, Imai A (2006) Participation of the spinal TRPV1 receptors in formalin-evoked pain transduction: a study using a selective TRPV1 antagonist, iodo-resiniferatoxin. J Pharm Pharmacol 58: 489–493. 46. Santos AR, Calixto JB (1997) Ruthenium red and capsazepine antinociceptive effect in formalin and capsaicin models of pain in mice. Neurosci Lett 235: 73–76. 47. Niiyama Y, Kawamata T, Yamamoto J, Omote K, Namiki A (2007) Bone cancer increases transient receptor potential vanilloid subfamily 1 expression within distinct subpopulations of dorsal root ganglion neurons. Neuroscience 148: 560–572. 48. Bode AM, Cho YY, Zheng D, Zhu F, Ericson ME, et al. (2009) Transient receptor potential type vanilloid 1 suppresses skin carcinogenesis. Cancer Res 69: 905–913. 49. Tyihak E, Bocsi J, Timar F, Racz G, Szende B (2001) Formaldehyde promotes and inhibits the proliferation of cultured tumour and endothelial cells. Cell Prolif 34: 135–141. 50. Travis RC, Allen DS, Fentiman IS, Key TJ (2004) Melatonin and breast cancer: a prospective study. J Natl Cancer Inst 96: 475–482. 51. Tu Y, Sun RQ, Willis WD (2004) Effects of intrathecal injections of melatonin analogs on capsaicin-induced secondary mechanical allodynia and hyperalgesia in rats. Pain 109: 340–350. 52. Perissin L, Boccalon S, Scaggiante B, Petrelli L, Ortolani F, et al. (2004) Diurnal changes of tonic nociceptive responses in mice: evidence for a proalgesic role of melatonin. Pain 110: 250–258. 53. Ayar A, Martin DJ, Ozcan M, Kelestimur H (2001) Melatonin inhibits high voltage activated calcium currents in cultured rat dorsal root ganglion neurones. Neurosci Lett 313: 73–77. 54. Audinot V, Bonnaud A, Grandcolas L, Rodriguez M, Nagel N, et al. (2008) Molecular cloning and pharmacological characterization of rat melatonin MT1 and MT2 receptors. Biochem Pharmacol 75: 2007–2019. 55. Szende B, Tyiha´k E, Tre´zl L, Szo¨ke E, La´szlo´ I, et al. (1998) Formaldehyde generators and capturers as influencing factors of mitotic and apoptotic processes. Acta Biol Hung 49: 323–329. 56. Torres-Lopez JE, Ortiz MI, Castaneda-Hernandez G, Alonso-Lopez R, Asomoza-Espinosa R, et al. (2002) Comparison of the antinociceptive effect of celecoxib, diclofenac and resveratrol in the formalin test. Life Sci 70: 1669–1676. 57. Staab CA, Alander J, Brandt M, Lengqvist J, Morgenstern R, et al. (2008) Reduction of S-nitrosoglutathione by alcohol dehydrogenase 3 is facilitated by substrate alcohols via direct cofactor recycling and results in GSH-controlled formation of glutathione transferase inhibitors. Biochem J. pp 493–504. 58. Ku RH, Billings RE (1984) Relationships between formaldehyde metabolism and toxicity and glutathione concentrations in isolated rat hepatocytes. Chem Biol Interact 51: 25–36. 59. Barber RD, Donohue TJ (1998) Pathways for transcriptional activation of a glutathione-dependent formaldehyde dehydrogenase gene. J Mol Biol 280: 775–784. 60. Szende B, Tyihak E, Kiraly-Veghely Z (2000) Dose-dependent effect of resveratrol on proliferation and apoptosis in endothelial and tumor cell cultures. Exp Mol Med 32: 88–92. 61. Saiko P, Szakmary A, Jaeger W, Szekeres T (2008) Resveratrol and its analogs: defense against cancer, coronary disease and neurodegenerative maladies or just a fad? Mutat Res 658: 68–94. 62. Yeh CC, Hou MF, Wu SH, Tsai SM, Lin SK, et al. (2006) A study of glutathione status in the blood and tissues of patients with breast cancer. Cell Biochem Funct 24: 555–559. 63. Balendiran GK, Dabur R, Fraser D (2004) The role of glutathione in cancer. Cell Biochem Funct 22: 343–352. 64. Andersson DA, Gentry C, Moss S, Bevan S (2008) Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J Neurosci 28: 2485–2494. 65. Chuang HH, Lin S (2009) Oxidative challenges sensitize the capsaicin receptor by covalent cysteine modification. Proc Natl Acad Sci U S A 106: 20097–20102. 66. Melzack R (1975) The McGill Pain Questionnaire: major properties and scoring methods. Pain 1: 277–299. 67. Medhurst SJ, Walker K, Bowes M, Kidd BL, Glatt M, et al. (2002) A rat model of bone cancer pain. Pain 96: 129–140. 68. Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16: 109–110. 69. Luo H, Cheng J, Han JS, Wan Y (2004) Change of vanilloid receptor 1 expression in dorsal root ganglion and spinal dorsal horn during inflammatory nociception induced by complete Freund’s adjuvant in rats. Neuroreport 15: 655–658. 70. Yu L, Yang F, Luo H, Liu FY, Han JS, et al. (2008) The role of TRPV1 in different subtypes of dorsal root ganglion neurons in rat chronic inflammatory nociception induced by complete Freund’s adjuvant. Mol Pain 4: 61. PLoS ONE | www.plosone.org 14 April 2010 | Volume 5 | Issue 4 | e10234