Therapeutic targeting of TRPV1 by resiniferatoxin, from preclinical studies to clinical trials

Current Topics in Medicinal Chemistry

Volumn 11, Issue 17, 2011, Pages 2159-2170

  Kissin, Igor ^a   Szallasi, Arpad ^b  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b DREXEL UNIVERSITY COLLEGE OF MEDICINE   (United States)

Author keywords

Capsaicin; Inflammatory thermal hy peralgesia; Neuropathic pain; Overactive bladder; Resiniferatoxin; The capsaicin (Vanilloid) receptor TRPV1

Indexed keywords

BUPIVACAINE; CAPSAICIN; LIDOCAINE; MORPHINE; RESINIFERATOXIN; VANILLOID RECEPTOR 1; VANILLOID RECEPTOR 1 ANTAGONIST;

ANALGESIA; ANALGESIC ACTIVITY; BLADDER FUNCTION; CLINICAL TRIAL (TOPIC); DESENSITIZATION; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENCY; DRUG TARGETING; FEVER; HEAT; HUMAN; HYPERALGESIA; INFLAMMATION; KNEE ARTHRITIS; MOLECULAR CLONING; NEUROPATHIC PAIN; NOCICEPTION; NOCICEPTIVE STIMULATION; NONHUMAN; OVERACTIVE BLADDER; PAIN; PH; REVIEW; SENSORY NERVE CELL; TISSUE INJURY;

ANIMALS; CAPSAICIN; CLINICAL TRIALS AS TOPIC; DITERPENES; DRUG EVALUATION, PRECLINICAL; HUMANS; PAIN; STRUCTURE-ACTIVITY RELATIONSHIP; TRPV CATION CHANNELS;

EID: 80052223776     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/156802611796904924     Document Type: Review

References (106)

1. Cairns, B.E. Ed., Peripheral Receptor Targets for Analgesia. Novel Approaches to Pain Management. John Wiley&Sons, Hoboken, NJ, 2009.
2. Patapoutian, A.; Tate, S.; Woolf, C. Transient receptor potential channels, targeting pain at the source. Nature Rev. Drug Discov., 2009, 8, 55-61.
3. Szallasi, A.; Cortright, D.N.; Blum, C.A.; Eid, S.R. The vanilloid receptor TRPV1, 10 years from channel cloning to antagonist proof-of-concept. Nat. Rev. Drug Discov., 2007, 6, 357-372.
4. Faltynek, C.; Gomtsyan, A. Eds, Vanilloid Receptor TRPV1 in Drug Discovery, Targeting Pain and Other Pathological Disorders. John Wiley&Sons, Hoboken, NJ, 2009.
5. Szallasi, A.; Blumberg, P.M. Vanilloid (capsaicin) receptors and mechanisms. Pharmacol. Rev., 1999, 51, 159-212.
6. Szallasi, A. Capsaicin, the active principle in Chili peppers, is hot on the tongue and soothing in pain, an eight thousand year-long "tr(i)p" from the Tehuacán Valley to the pain clinic. Analecta His-torio Medica 2008, (Suppl). 1, 89-94.
7. Högyes, E. Beitrage zur physiologischen wirkung der bestandteile des Capsicum annum. Arch. Exp. Pathol. Pharmakol., 1878, 9, 117-130.
8. Jancsó, N.A. Desensitization of sensory nerve endings. Kísérletes Orvostudomány, 1949, 2(2 Suppl),15.
9. Maggi, C.A.; Meli, A. The sensory-efferent function of capsaicin- sensitive sensory neurons. Gen. Pharmacol., 1988, 19(1), 1-43.
10. Holzer, P. Capsaicin, cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev., 1991, 43(2), 143-201.
11. Szolcsanyi J. A pharmacological approach to elucidation of the role of different nerve fibres and receptor endings in mediation of pain. J. Physiol., (Paris) 1977, 73, 251-259.
12. Geppetti, P.; Holzer, P. Eds., Neurogenic inflammation. CRC Press, Boca Raton, FL, 1996.
13. Zhang, W.Y.; Li, W.; Po, A. The effectiveness of topically applied capsaicin, a meta-analysis. Eur. J. Clin. Pharmacol., 1994, 46, 517-522.
14. Knotkova, H.; Pappagallo, M.; Szallasi, A. Capsaicin (TRPV1 Agonist) therapy for pain relief, farewell or revival? Clin. J. Pain., 2008, 24, 142-154.
15. Ozawa, H.; Jung, S.Y.; Fraser, M.O.; Rivas, D.A.; Chancellor, M.B. Intravesical capsaicin therapy, a review. J. Spinal Cord Med., 1999, 22, 114-118.
16. Kim, D.Y.; Chancellor, M.B. Intravesical neuromodulatory drugs, capsaicin and resiniferatoxin to treat the overactive bladder. J. En-dourol., 2000, 14, 97-103.
17. Szallasi, A.; Fowler, C.J. After a decade of intravesical vanilloid therapy, still more questions than answers. Lancet Neurol., 2002, 1, 167-172.
18. Marabini, S.; Ciabatti, P.G.; Polli, G.; Fusco, B.; Geppetti, P. Beneficial effects of intranasal applications of capsaicin in patients with vasomotor rhinitis. Eur. Arch. Otorhinolaryngol., 1991, 248, 191-194.
19. Diamond, S.; Freitag, F.; Phillips, S.B.; Bernstein, J.E.; Saper, J.R. Intranasal civamide for the acute treatment of migraine headache. Cephalalgia, 2000, 20, 597-602.
20. Saper, J.R.; Klapper, J.; Mathew, N.T.; Rapoport, A.; Phillips, S.B.; Bernstein, J.E. Intranasal civamide for the treatment of episodic cluster headaches. Arch. Neurol., 2002, 59, 990-904.
21. 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.
22. Noto, C.; Pappagallo, M.; Szallasi, A. NGX-4010, a high-concentration capsaicin dermal patch for lasting relief of peripheral neuropathic pain. Curr. Opin. Investig. Drugs, 2009, 10, 702-710.
23. Szallasi, A.; Blumberg, P.M. Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper. Neuroscience, 1989, 30, 515-520.
24. Hergenhahn, M.; Adolph, W.; Hecker, E. Resiniferatoxin and other esters of noval polyfunctional diterpenes from Euphorbia resinifera and unispina. Tetrahedron Lett., 1975, 19, 1595-1598.
25. Zur Hausen, H.; Bornkamm, G.W.; Schmidt, R.; Hecker, E. Tumor initiators and promoters in the induction of Epstein-Barr virus. Proc. Natl. Acad. Sci. USA, 1979, 76, 782-785.
26. Driedger, P.E.; Blumberg, P.M. Specific binding of phorbol ester tumor promoters. Proc. Natl. Acad. Sci. USA, 1980, 77, 567-571.
27. Szallasi, A.; Blumberg, P.M. Specific binding of resiniferatoxin, an ultrapotent capsaicin analog, by dorsal root ganglion membranes. Brain Res., 1990, 524, 106-111.
28. 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.
29. 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 cap-saicin receptor. Science, 2000, 288, 306-313.
30. Davis, J.B.; Gray, J.; Gunthorpe, M.J.; Hatcher, J.P.; Davey, P.T.; Overend, P.; Harries, M.H.; Latcham, J.; Clapham, C.; Atkinson, K; Hughes, S.A.; Rance, K.; Grau, E.; Harper, A.J.; Pugh, P.L.; Rogers, D.C.; Bingham, S.; Randall, A; Sheardown, S.A. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature, 2000, 405, 183-187.
31. Christoph, T.; Grunweller, A.; Mika, J.; Schafer, M.K.; Wade, E.J.; Weihe, E.; Erdmann, V.A.; Frank, R.; Gillen, C.; Kurreck, J. Silencing of vanilloid receptor TRPV1 by RNAi reduces neuropathic and visceral pain in vivo. Biochem. Biophys. Res. Commun., 2006, 350, 238-243.
32. Kasama, S.; Kawakubo, M.; Suzuki, T.; Nishizawa, T.; Ishida, A.; Nakayama, J. RNA interference-mediated knock-down of transient receptor potential vanilloid 1 prevents forepaw inflammatory hy-peralgesia in rat. Eur. J. Neurosci., 2007, 25, 2956-2963.
33. Pingle, S.C.; Matta, J.A.; Ahern, G.P. Capsaicin receptor TRPV1, a promiscuous TRP channel. Handb. Exp. Pharmacol., 2007, 179, 155-171.
34. Jara-Oseguera, A.; Nieto-Posada, A.; Szallasi, A.; Islas, L.; Rosen-baum, T. Molecular mechanisms of TRPV1 activation. Open Pain J., 2010, 3, 68-81.
35. Siemens, J.; Zhou, S.; Piskorowski, R.; Nikai, T.; Lumpkin, E.A.; Basbaum, A.I. et al. Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature, 2006, 444, 208-212.
36. Cromer, B.A.; McIntyre, P. Painful toxins acting at TRPV1. Toxi-con, 2008, 51, 163-173.
37. Planells-Cases, R.; Valente, P.; Ferrer-Montiel, A.; Qin, F.; Szal-Lasi, A. Complex regulation of TRPV1 and related thermoTRPs, implications for therapeutic intervention. In, The Transient Receptor Potential Ion Channels. Eds., Islam, S. Springer, in press.
38. Varga, A.; Bolcskei, K.; Szoke, E.; Almasi, R.; Czeh, G.; Szolcsanyi, J. Relative roles of protein kinase A and protein kinase C in modulation of transient receptor potential vanilloid type 1 receptor responsiveness in rat sensory neurons in vitro and peripheral nociceptors in vivo. Neuroscience, 2006, 140, 645-657.
39. Prescott, E.D.; Julius, D. A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science, 2003, 300, 1284-1288.
40. Szolcsányi, J. Hot target on nociceptors, perspectives, caveats, and unique features. Br. J. Pharmacol., 2008, 155, 1142-1148.
41. Malmberg, A.B.; Mizisin, A.P.; Calcutt, N.A.; von Stein, T.; Rob-bins, W.R.; Bley, K.R. Reduced heat sensitivity and epidermal nerve fibre immunostaining following single applications of a high concentration capsaicin patch. Pain, 2004, 111, 360-367.
42. Malmberg, A.; Bley, K. Eds., Turning up the Heat on Pain, TRPV1 Receptors in Pain and Inflammation. Birkhäuser, Basel, Switzerland, 2005.
43. Szallasi, A. Vanilloid-sensitive neurons, a fundamental subdivision of the peripheral nervous system. J. Periph. Nerv. System, 1996, 1, 6-18.
44. Gamse, R.; Petsche, U.; Lembeck, F.; Jancsó, G. Capsaicin applied to the peripheral nerve inhibits axoplasmic transport of substance P and somatostatin. Brain Res., 1982, 238, 447-462.
45. Szallasi, A.; Farkas-Szallasi, T.; Tucker, J.B.; Lundberg, J.M.; Hökfelt, T.; Krause, J.E. Effects of systemic resiniferatoxin treatment on substance P mRNA in rat dorsal root ganglia and substance P receptor mRNA in the spinal cord. Brain Res., 1999, 815, 177-184.
46. Jancsó G. Pathobiological reactions of C-fiber primary sensory neurons to peripheral nerve injury. Exp. Physiol., 1992, 77, 405-431.
47. Farkas-Szallasi, T.; Bennett, G.J.; Blumberg, P.M.; Hökfelt, T.; Lundberg, J.M.; Szallasi, A. Vanilloid receptor loss is independent of the messenger plasticity that follows systemic resiniferatoxin administration. Brain Res., 1996, 719, 213-218.
48. Szallasi, A.; Blumberg, P.M. Resiniferatoxin and analogs provide novel insights into the pharmacology of the vanilloid (capsaicin) receptor. Life Sci., 1990, 47, 1399-1408.
49. Maggi, C.A.; Patacchini, R.; Tramontana, M.; Amann, R.; Giuliani, S.; Santicioli, P. Similarities and differences in the action of res-iniferatoxin and capsaicin on central and peripheral endings of primary sensory neurons. Neuroscience, 1990, 37, 531-539.
50. Szolcsanyi, J.; Szallasi, A.; Szallasi, Z.; Joo, F.; Blumberg, P.M. Resiniferatoxin, an ultrapotent selective modulator of capsaicin-sensitive primary afferent neurons. J. Pharmacol. Exp. Ther., 1990, 255, 923-8.
51. Bíró, T.; Ács, G.; Ács, P.; Modarres, S.; Blumberg, P.M. Recent advances in understanding vanilloid receptors, a therapeutic target for treatment of pain and inflammation in skin. J Invest. Dermatol. Symp. Proc., 1997, 2, 56-60.
52. 45Ca uptake and for high affinity binding in culture dorsal root ganglion neurons. Mol. Brain Res., 1996, 35, 173-182.
53. Liu, L., Szallasi, A., Simon, S.A. A non-pungent resiniferatoxin analogue, phorbol 12-phenylacetate 13-acetate 20-homovanillate, reveals vanilloid receptor subtypes on rat trigeminal ganglion neurons. Neuroscience, 1998, 84, 569-581.
54. Szallasi, A.; Blumberg, P.M.; Annicelli, L.L.; Krause, J.E.; Cor-tright, D.N. The cloned rat vanilloid receptor VR1 mediates both R-type binding and C-type calcium response in dorsal root ganglion neurons. Mol. Pharmacol., 1999, 56, 581-587.
55. Kissin, I. Vanilloid-induced conduction analgesia, Selective, dose-dependent, long-lasting, with a low level of potential neurotoxicity. Anesth. Analg., 2008, 107, 271-261.
56. Acs, G.; Palkovits, M.; Blumberg, P.M. Comparison of [3H]resiniferatoxin binding by the vanilloid(capsaicin) receptor in dorsal root ganglia, spinal cord, dorsal vagal complex, sciatic and vagal nerve and urinary bladder of the rat. Life Sci., 1994, 55, 1017-1026.
57. Guo, A.; Vulchanova, L.; Wang, J.; Li, X.; Elde, R. Immunocyto-chemical localization of the vanilloid receptor 1 (VR1), relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur. J. Neurosci., 1999, 11, 946-958.
58. Bernardini, N.; Neuhuber, W.; Reeh, P.W.; Sauer, S.K. Morphological evidence for functional capsaicin receptor expression and calcitonin gene-related peptide exocytosis in isolated peripheral nerve axons of the mouse. Neuroscience, 2004, 126, 585-590.
59. Jung, J.; Hwang, S.W.; Kwak, J.; Lee, S-Y.; Kang, C-J.; Kim, W.B.; Kim, D.; Oh, U. Capsaicin binds to the intracellular domain of the capsaicin-activated ion channel. J. Neurosci., 1999, 19, 529-538.
60. Lazar, J.; Braun, D.C.; Toth, A.; Wang, Y.; Pearce, L.V.; Pavlyuk-ovets, V.A.; Blumberg, P.M.; Garfield, S.H.; Wincovitch, S.; Choi, H.K.; Lee, J. Kinetics of penetration influence the apparent potency of vanilloids on TRPV1. Mol. Pharmacol., 2006, 69, 1166-1173.
61. Planells-Cases, R.; Camprubí-Robles, M. Antonio Ferrer-Montiel, TRP channel trafficking. In, TRP Channels in Health and Disease, Implications for Diagnosis and Therapy. Eds., Szallasi, A. Nova Publishers, in press.
62. Ma, Q-P. Expression of capsaicin receptor (VR1) by myelinated primary afferent neurons in rats. Neurosci. Lett., 2002, 319, 87-90.
63. Petsche, U.; Fleischer, E.; Lembeck, F.; Handwerker, H.O. The effect of capsaicin application to a peripheral nerve on impulse conduction in functionally identified afferent nerve fibers. Brain Res., 1983, 265, 233-240.
64. Chung, J.M.; Lee, K.H.; Hori, Y.; Willis, W.D. Effects of capsaicin applied to a peripheral nerve on the responses of primate spi-nothalamic tract cells. Brain Res., 1985, 329, 27-38.
65. Baranowski, R.; Lynn, B.; Pini, A. The effects of locally applied capsaicin on conduction in cutaneous nerves in four mammalian species. Br. J. Pharmacol., 1986, 89, 267-276.
66. Shin, H.C.; Park, H.J.; Raymond, S.A.; Strichartz, G.R. Potentia-tion by capsaicin of lidocaine's tonic impulse block in isolated rat sciatic nerve. Neurosci. Lett., 1994, 174, 14-16.
67. Nagasaka, H.; Awad, H.; Yaksh, T.L. Peripheral and spinal actions of opioids in the blockade of the autonomic response evoked by compression of the inflamed knee joint. Anesthesiology, 1996, 85, 808-816.
68. Grosskreutz, J.; Quasthoff, S.; Kuhn, M.; Grafe, P. Capsaicin blocks tetrodotoxin-resistant sodium potential and calcium potentials in unmyelinated C-fibers of biopsied human sural nerve in vitro. Neurosci. Lett., 1996, 808, 48-52.
69. Hayes, A.G.; Hawcock, A.B.; Hill, R.G. The depolarizing action of capsaicin on rat isolated sciatic nerve. Life Sci., 1984, 35, 1561-158.
70. Jeffrey, J.A.; Yu, S.Q.; Sikand, P.; Parihar, A.; Evans, M.S.; Prem-kumar, L.S. Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia. PLoS ONE, 2009, 4, e7021.
71. Su, X.; Wachtel, R.E.; Gebhart, G.F. Capsaicin sensitivity and voltage-gated sodium currents in colon sensory neurons from rat dorsal root ganglia. Am. J. Physiol., 1999, 277, G1180-88.
72. Liu, L.; Oortgiesen, A.M.; Simon, S.A. Capsaicin inhibits activation of voltage-gated sodium currents in capsaicin-sensitive tri-geminal ganglion neurons. J. Neurophysiol., 2001, 85,745-758.
73. Lundbaek, J.A.; Birn, P.; Tape, S.E.; Toombes, G.E.; Sogaard, R.; Koeppe, R.E. II; Gruner, S.M.; Hansen, A.J.; Andersen, O.S. Cap-saicin regulates voltage-dependent sodium channels by altering lipid bilayer elasticity. Mol. Pharmacol., 2005, 68, 680-689.
74. Wang, S-Y.; Mitchell, J.; Wang, G.K. Preferential block of inacti-vation-deficient Na+ currents by capsaicin reveals a non-TRPV1 receptor within the Na+ channel. Pain, 2007, 127, 73-83.
75. Jancso, G.; Kiraly, E.; Jancso-Gabor, A. Direct evidence for an axonal site of action of capsaicin. Naunyn-Schmiedeberg's Arch. Pharmacol., 1980, 313, 91-94.
76. Kissin, I.; Bright, C.A.; Bradley, E.L. Jr. Selective and long-lasting neural blockade with resiniferatoxin prevents inflammatory pain hypersensitivity. Anesth. Analg., 2002, 94, 1253-1258.
77. Xu, X.J.; Farkas-Szallasi, T.; Lundberg, J.M.; Hokfelt, T.; Wiesen-feld-Hallin, Z.; Szallasi, A. Effects of the capsaicin analogue res-iniferatoxin on spinal nociceptive mechanisms in the rat, behavioral, electrophysiological and in situ hybridization studies. Brain Res., 1997, 752, 52-60.
78. Kissin, I.; Davison, N.; Bradley, EL Jr. Perineural resiniferatoxin prevents hyperalgesia in a model of postoperative pain. Anesth. Analg., 2005, 10,774-780.
79. Neubert, J.K.; Laszlo, K.; Jun, J.; Kin, H-S.; Olah, Z.; Iadarola, M.J. Peripherally induced resiniferatoxin analgesia. Pain, 2003, 104, 219-228.
80. Neubert, J.K.; Mannes, A.J.; Laszlo, J.K.; Jenkins, A.C.; Zawatski, L.; Abu-Asab, M.; Iadarola, M.J. Perineural resinferatoxin selectively inhibits inflammatory hyperalgesia. Mol. Pain, 2008, 4, 1-10.
81. Bennett, G.J.; Xie, Y.K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain, 1988, 33, 87-107.
82. Maves, T.J.; Pechman, P.S.; Gebhart, G.F.; Meller, S.T. Possible chemical contribution from chromic gut sutures produces disorders of pain sensation like those seen in man. Pain, 1993, 54, 57-69.
83. Clatworthy, A.L.; Illich, P.A.; Castro, G.A.; Walters, E.T. Role of peri-axonal inflammation in the development of thermal hyperalge-sia and guarding behavior in a rat model of neuropathic pain. Neu-rosci. Lett., 1995, 184, 5-8.
84. Kissin, I.; Freitas, C.F.; Bradley, E.L. Jr. Perineural resiniferatoxin prevents the development of hyperalgesia produced by loose liga-tion of the sciatic nerve in rats. Anesth. Analg., 2007, 104, 1210-1216.
85. Munger, B.L.; Bennett, G.J.; Kajander, K.C. An experimental painful peripheral neuropathy due to nerve constriction. I. Axonal pathology in the sciatic nerve. Exp. Neurol., 1992, 118, 204-214.
86. Ossipov, M.H.; Bian, D.; Malan, T.P.; Lai, J.; Porreca F. Lack of involvement of capsaicin-sensitive primary afferent in nerve-ligation induced injury induced tactile allodynia in rats. Pain, 1999, 79, 127-133.
87. Wu, M.; Komori, N.; Qin, C.; Farber, J.P.; Linderoth, B.; Foreman, R.D. Sensory fibers containing vanilloid receptor-1 (VR-1) mediate spinal cord stimulation-induced vasodilation. Brain Res., 2006, 1107, 177-184.
88. Kissin, E.Y.; Freitas, C.F.; Kissin, I. The effets of intraarticular resiniferatoxin in experimental kee-joint arthritis. Anesth. Analg., 2005, 101, 1433-1439.
89. Jancso, G.; Kiraly, E.; Jancso-Gabor, A. Pharmacologically induced selective degeneration of chemosensitive primary sensory neurones. Nature, 1977, 270, 741-743.
90. Szolcsanyi, J.; Jancso-Gabor, A.; Joo, F. Functional and fine structural characteristics of the sensory neuron blocking effect of cap-saicin. Naunyn-Schmiedeberg's Arch. Pharmacol., 1975, 287, 157-169.
91. Ainsworth, A.; Hall, P.; Wall, P.D.; Allt, G.; MacKenzie, M.L.; Gibson, S.; Polak, J.M. Effects of capsaicin applied locally to adult peripheral nerve. II. Anatomy and enzyme and peptide chemistry of peripheral nerve and spinal cord. Pain, 1981, 11, 379-388.
92. Pini, A.; Lynn, B. Long-term reduction in the number of C-fibre nociceptors following capsaicin treatment of a cutaneous nerve in adult rats. Eur. J. Neurosci., 1990, 2, 89-97.
93. Kissin, I.; Freitas, C.F.; Mulhern, H.; DeGirolami, U. Sciatic nerve block with resiniferatoxin, Electron microscopic study of unmyeli-nated fibers in the rat. Anesth. Analg., 2007, 105, 825-831.
94. Cabanac, M.; Cormareche-Leydier, M.; Poirier, L.J. The effect of capsaicin on temperature regulation of the rat. Pflugers Arch., 1976, 366, 217-221.
95. Glinsukon, T.; Stitmunnaithum, V.; Toskulkao, C.; Buranawuti, T.; Tangkrisanavinont, V. Acute toxicity of capsaicin in several animal species. Toxicon, 1980, 18, 215-220.
96. Grant, G.J.; Vermeulen, K.; Langerman, L.; Zakowski, M.; Turn-dorf, H. Prolonged analgesia with liposomal bupivacaine in a mouse model. Reg. Anesth., 1994, 19, 264-269.
97. Lee, L.Y.; Lundberg, J.M. Capsazepine abolishes pulmonary chemoreflexes induced by capsaicin in anesthetized rats. J. Appl. Physiol., 1994, 76, 1848-1855.
98. Brown, D.C.; Iadarola, M.J.; Perkowski, S.Z.; Erin, H.; Shofer, F.; Laszlo, K.J.; Olah, Z.; Mannes, A.J. Physiologic and antinocicep-tive effects of intrathecal resiniferatoxin in a canine bone cancer model. Anesthesiology, 2005, 103, 1052-1059.
99. Chung, K.; Klein, C.M.; Coggeshall, R.E. The receptive part of the primary afferent axon is most vulnerable to systemic capsaicin in adult rats. Brain Res., 1990, 511, 222-226.
100. rd Ed.,. Philadelphia,Lippincott-Raven 1998, 985-1006.
101. Reilly, D.M.; Ferdinando, D.; Johnston, C.; Shaw, C.; Buchanan, K.D.; Green, M.R. The epidermal nerve fibre network, characterization of nerve fibres in human skin by confocal microscopy and assessment of racial variations. Br. J. Dermatol., 1997, 137, 163-170.
102. 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.
103. Dux, M.; Sann, H.; Schemann, M.; Jancsó, G. Changes in fibre populations of the rat hairy skin following selective chemodenerva-tion by capsaicin. Cell Tissue Res., 1999, 296, 471-477.
104. Dasgupta, P.; Chandiramani, V.A.; Beckett, A.; Scaravilli, F.; Fowler, C.J. The effect of intravesical capsaicin on the suburothe-lial innervation in patients with detrusor hyper-reflexia. BJU Int., 2000, 85, 238-245.
105. Avelino, A.; Cruz, F. Peptide immunoreactivity and ultrastructure of rat urinary bladder nerve fibers after topical desensitization by capsaicin or resiniferatoxin. Auton. Neurosci., 2000, 86, 37-46.
106. Szallasi, A.; Cruz, F.; Geppetti, P. TRPV1, a therapeutic target for novel analgesic drugs? Trends Mol. Med., 2006, 12, 545-554.