Journal of Molecular Neuroscience

, Volume 48, Issue 3, pp 795–803 | Cite as

Effect of Surgical and Chemical Sensory Denervation on Non-neural Expression of the Transient Receptor Potential Vanilloid 1 (TRPV1) Receptors in the Rat

  • József Kun
  • Zsuzsanna Helyes
  • Anikó Perkecz
  • Ágnes Bán
  • Beáta Polgár
  • János Szolcsányi
  • Erika Pintér


Pretreatment with the ultrapotent capsaicin analog resiniferatoxin (RTX) has been applied as a selective pharmacological tool in inflammation and pain studies to desensitize transient receptor potential vanilloid 1 (TRPV1) receptor-expressing sensory nerve endings. The discovery of TRPV1 receptor on non-neural cells challenges systemic RTX desensitization as a method acting exclusively on a population of sensory neurons, but not on non-neural cells. Systemic RTX desensitization was used for chemical denervation and transection of the sciatic and saphenous nerves for surgical denervation in rats. Quantitative real-time PCR and immunohistochemistry were applied to investigate the presence and alterations of the TRPV1 receptor mRNA and protein following chemical and surgical denervation. We provided the first evidence for non-neural TRPV1 immunopositivity and mRNA expression in the rat dorsal paw and plantar skin as well as the oral mucosa. Neither chemical nor surgical denervation influenced the level of TRPV1 receptor mRNA and protein expression in non-neural cells of either skin regions or mucosa. Therefore, RTX and consequently capsaicin remain to be considered as selective neurotoxins for a population of primary afferent neurons.


Resiniferatoxin pretreatment Neural TRPV1 Non-neural TRPV1 Denervation Skin Oral mucosa Rat 



This work was sponsored by Hungarian Grants OTKA K81984, K73044, and NK78059 and Developing Competitiveness of Universities in the South Transdanubian Region (SROP-4.2.1.B-10/2/KONV-2010-0002).


  1. Alawi K, Keeble J (2009) The paradoxical role of the transient receptor potential vanilloid 1 receptor in inflammation. Pharmacol Ther 125:181–195PubMedCrossRefGoogle Scholar
  2. Anand P, Bley K (2011) Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8 % patch. Br J Anaesth 107:490–502PubMedCrossRefGoogle Scholar
  3. Athanasiou A, Smith PA, Vakilpour S et al (2007) Vanilloid receptor agonists and antagonists are mitochondrial inhibitors: how vanilloids cause non-vanilloid receptor mediated cell death. Biochem Biophys Res Commun 354:50–55PubMedCrossRefGoogle Scholar
  4. Ban A, Marincsak R, Biro T et al (2010) Up-regulation of transient receptor potential type-1 receptor expression in oral lichen planus. Neuroimmunomodulation 17:103–108PubMedCrossRefGoogle Scholar
  5. Banvolgyi A, Palinkas L, Berki T et al (2005) Evidence for a novel protective role of the vanilloid TRPV1 receptor in a cutaneous contact allergic dermatitis model. J Neuroimmunol 169:86–96PubMedCrossRefGoogle Scholar
  6. Birder LA, Kanai AJ, de Groat WC et al (2001) Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci USA 98:13396–401PubMedCrossRefGoogle Scholar
  7. Bodo E, Biro T, Telek A et al (2005) A hot new twist to hair biology: involvement of vanilloid receptor-1 (VR1/TRPV1) signaling in human hair growth control. Am J Pathol 166:985–998PubMedCrossRefGoogle Scholar
  8. Calixto JB, Kassuya CAL, Andre E, Ferreira J (2005) Contribution of natural products to the discovery of the transient receptor potential (TRP) channels family and their functions. Pharmacol Ther 106:179–208PubMedCrossRefGoogle Scholar
  9. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat activated ion channel in the pain pathway. Nature 389:816–824PubMedCrossRefGoogle Scholar
  10. Charrua N, Reguenga C, Cordeiro JM et al (2009) Functional transient receptor potential vanilloid 1 is expressed in human urothelial cells. J Urol 182:2944–2950PubMedCrossRefGoogle Scholar
  11. Denda M, Fuziwara S, Inoue K et al (2001) Immunoreactivity of VR1 on epidermal keratinocyte of human skin. Biochem Biophys Res Commun 285:1250–1252PubMedCrossRefGoogle Scholar
  12. Denda S, Denda M, Inoue K, Hibino T (2010) Glycolic acid induces keratinocyte proliferation in a skin equivalent model via TRPV1 activation. J Dermatol Sci 57:108–113PubMedCrossRefGoogle Scholar
  13. Donnerer J, Lembeck F (1982) Analysis of the effects of intravenously injected capsaicin in the rat. Naunyn Schmiedebergs Arch Pharmacol 320:54–57PubMedCrossRefGoogle Scholar
  14. Dux M, Santha P, Jancso G (2003) Capsaicin-sensitive neurogenic sensory vasodilatation in the dura mater of the rat. J Physiol (Lond) 552:859–867CrossRefGoogle Scholar
  15. Engler A, Aeschlimann A, Simmen BR et al (2007) Expression of transient receptor potential vanilloid 1 (TRPV1) in synovial fibroblasts from patients with osteoarthritis and rheumatoid arthritis. Biochem Biophys Res Commun 359:884–888PubMedCrossRefGoogle Scholar
  16. Gunthorpe MJ, Szallasi A (2008) Peripheral TRPV1 receptors as targets for drug development. Curr Pharm Des 14:32–41PubMedCrossRefGoogle Scholar
  17. Helyes Z, Elekes K, Sándor K et al (2010) Involvement of preprotachykinin A gene-encoded peptides and the neurokinin 1 receptor in endotoxin-induced murine airway inflammation. Neuropeptides 44:399–406PubMedCrossRefGoogle Scholar
  18. Inoue K, Koizumi S, Fuziwara S, Denda S, Inoue K, Denda M (2002) Functional vanilloid receptors in cultured normal human epidermal keratinocytes. Biochem Biophys Res Commun 291:124–129PubMedCrossRefGoogle Scholar
  19. Jancso N, Jancso-Gabor A, Szolcsanyi J (1967) Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Brit J Pharmacol 31:138–151PubMedGoogle Scholar
  20. Jancso G, Kiraly E, Jancso-Gabor A (1977) Pharmacologically induced selective degeneration of chemosensitive primary sensory neurons. Nature 270:741–743PubMedCrossRefGoogle Scholar
  21. Kark T, Bagi Z, Lizanecz E et al (2008) Tissue-specific regulation of microvascular diameter: opposite functional roles of neuronal and smooth muscle located vanilloid receptor-1. Mol Pharmacol 73(5):1405–1412Google Scholar
  22. Ko F, Diaz M, Smith P et al (1998) Toxic effects of capsaicin on keratinocytes and fibroblasts. J Burn Care Rehabil 19:409–413PubMedCrossRefGoogle Scholar
  23. Lai J-P, Douglas SD, Ho W-Z (1998) Human lymphocytes express substance P and its receptor. J Neuroimmunol 86:80–86PubMedCrossRefGoogle Scholar
  24. Lazzeri M, Vannucchi MG, Zardo C et al (2004) Immunohistochemical evidence of vanilloid receptor 1 in normal human urinary bladder. Eur Urol 46:792–798PubMedCrossRefGoogle Scholar
  25. Lee H, Caterina MJ (2005) TRPV channels as thermosensory receptors in epithelial cells. Pflüger’s Arch 451:160–167CrossRefGoogle Scholar
  26. Lee YM, Kim YK, Kim KH, Park SJ, Kim SJ, Chung JH (2009) A novel role for the TRPV1 channel in UV-induced matrix metalloproteinase (MMP)-1 expression in HaCaT cells. J Cell Physiol 219(3):766–75PubMedCrossRefGoogle Scholar
  27. Li WH, Lee JM, Kim JY et al (2007) Transient receptor potential vanilloid-1 mediates heat-shock-induced matrix metalloproteinase-1 expression in human epidermal keratinocytes. J Invest Dermatol 127:2328–2335PubMedCrossRefGoogle Scholar
  28. Lizanecz E, Bagi Z, Pasztor ET et al (2006) Phosphorylation-dependent desensitization by anandamide of vanilloid receptor-1 (TRPV1): function in rat skeletal muscle arterioles and in Chinese hamster ovary cells expressing TRPV1. Mol Pharmacol 69:1015–1023PubMedGoogle Scholar
  29. Maggi CA, Patacchini R, Tramontana M, Amann R, Giuliani S, Santicioli S (1990) Similarities and differences in the action of resiniferatoxin and capsaicin on central and peripheral endings of primary sensory neurons. Neuroscience 37(53):1–539Google Scholar
  30. Ohtori S, Chiba T, Takahashi K (2000) Neonatal capsaicin treatment decreased substance P receptor immunoreactivity in lamina III neurons of the dorsal horn. Neurosci Res 38:147–154PubMedCrossRefGoogle Scholar
  31. Pecze L, Szabo K, Szell M et al (2008) Human keratinocytes are vanilloid resistant. PLoS One 3(10):e3419PubMedCrossRefGoogle Scholar
  32. Pinter E, Szolcsanyi J (1995) Plasma extravasation in the skin and pelvic organs evoked by antidromic stimulation of the lumbosacral dorsal roots of the rat. Neuroscience 68:603–614PubMedCrossRefGoogle Scholar
  33. Porszasz R, Porkolab A, Ferencz A, Pataki T, Szilvassy Z, Szolcsanyi J (2002) Capsaicin-induced nonneural vasoconstriction in canine mesenteric arteries. Eur J Pharmacol 441:173–175PubMedCrossRefGoogle Scholar
  34. Radtke C, Sinis N, Sauter M et al (2011) TRPV channel expression in human skin and possible role in thermally induced cell death. J Burn Care Res 32(1):150–9PubMedCrossRefGoogle Scholar
  35. Saunders C, Kunde DA, Crawford A, Geraghty DP (2007) Expression of transient receptor potential vanilloid 1 (TRPV1) and 2 (TRPV2) in human peripheral blood. Mol Immunol 44:1429–1435PubMedCrossRefGoogle Scholar
  36. Saunders C, Fassett RG, Geraghty DP (2009) Up-regulation of TRPV1 in mononuclear cells of end-stage kidney disease patients increases susceptibility to N-arachidonoyl-dopamine (NADA)-induced cell death. Biochim Biophys Acta 1792:1019–1026PubMedCrossRefGoogle Scholar
  37. Seki N, Shirasaki H, Kikuchi M, Sakamoto T, Watanabe N, Himi T (2006) Expression and localization of TRPV1 in human nasal mucosa. Rhinology 44(2):128–34PubMedGoogle Scholar
  38. Southall MD, Li T, Gharibova LS, Pei Y, Nicol GD, Travers JB (2003) Activation of epidermal vanilloid receptor-1 induces release of proinflammatory mediators in human keratinocytes. J Pharmacol Exp Ther 304:217–222PubMedCrossRefGoogle Scholar
  39. Stander S, Moormann C, Schumacher M (2004) Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp Dermatol 13(3):129–139PubMedCrossRefGoogle Scholar
  40. Starowicz K, Nigam S, Di Marz V (2007) Biochemistry and pharmacology of endovanilloids. Pharmacol Ther 114:13–33PubMedCrossRefGoogle Scholar
  41. Sugimoto T, Xiao C, Ichikawa H (1998) Neonatal primary neuronal death induced by capsaicin and axotomy involves an apoptotic mechanism. Brain Res 807:147–154PubMedCrossRefGoogle Scholar
  42. Szallasi A (1995) Autoradiographic visualization and pharmacological characterization of vanilloid (capsaicin) receptors in several species, including man. Acta Physiol Scand 155(Suppl 629):1–68Google Scholar
  43. Szallasi A, Blumberg PM (1999) Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 51:159–211PubMedGoogle Scholar
  44. Szallasi A, Farkas-Szallasi T, Tucker JB et al (1999) Effects of systemic resiniferatoxin treatment on substance P mRNA in rat dorsal root ganglia and substance P receptor mRNA in the spinal dorsal horn. Brain Res 815:177–184PubMedCrossRefGoogle Scholar
  45. Szallasi A, Cortright DN, Blum CA, Eid SR (2007) The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 6:357PubMedCrossRefGoogle Scholar
  46. Szolcsanyi J (2004) Forty years in capsaicin research for sensory pharmacology and physiology. Neuropeptides 38:377–384PubMedCrossRefGoogle Scholar
  47. Szolcsanyi J, Oroszi G, Nemeth J, Szilvassy Z, Blasig IE, Tosaki A (2001) Functional and biochemical evidence for capsaicin-induced neural endothelin release in isolated working rat heart. Eur J Pharmacol 419:215–221PubMedCrossRefGoogle Scholar
  48. Vyklicky L, Novakova-Tousova K, Benedikt J, Samad A, Touska F, Vlachova V (2008) Calcium-dependent desensitization of vanilloid receptor TRPV1: a mechanism possibly involved in analgesia induced by topical application of capsaicin. Physiol Res 57(suppl 3):S59–S68PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • József Kun
    • 1
  • Zsuzsanna Helyes
    • 1
  • Anikó Perkecz
    • 1
  • Ágnes Bán
    • 2
  • Beáta Polgár
    • 3
  • János Szolcsányi
    • 1
  • Erika Pintér
    • 1
  1. 1.Department of Pharmacology and Pharmacotherapy, Faculty of MedicineUniversity of PécsPécsHungary
  2. 2.Department of Dentistry, Oral and Maxillofacial Surgery, Faculty of MedicineUniversity of PécsPécsHungary
  3. 3.Department of Medical Microbiology and Immunology, Faculty of MedicineUniversity of PécsPécsHungary

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