Skip to main content
SpringerLink
Log in
Book cover

Handbook of Neurotoxicity pp 611–636Cite as

TRPV1 Activators (“Vanilloids”) as Neurotoxins

  • Reference work entry
  • First Online:

Abstract

A distinct subset of primary sensory neurons is distinguished by their unique sensitivity to capsaicin, the pungent ingredient in hot chili peppers. The initial excitation by capsaicin of these neurons is followed by a long-lasting, but fully reversible, refractory state (traditionally termed as desensitization) or under certain conditions, like neonatal treatment, frank neurotoxicity. This neurotoxic action was extensively used to identify capsaicin-sensitive neuronal pathways and to explore their physiological function. In 1997, a specific receptor for capsaicin and related compounds (collectively referred to as vanilloids) was identified as transient receptor potential cation channel subfamily V member 1 (TRPV1), a multifunctional channel involved in thermosensation (heat) and taste perception (e.g., peppers and vinegar). Importantly, TRPV1 also functions as a molecular integrator for a broad range of seemingly unrelated noxious stimuli including venoms from spiders and jellyfish. Indeed, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that follows inflammation and/or tissue injury. Ablation of sensory neurons by vanilloids is, however, not only a research tool but also has a clear therapeutic potential. Currently, site-specific resiniferatoxin (an ultrapotent capsaicin analog) injections are being evaluated as “molecular scalpels” to achieve permanent analgesia in cancer patients with chronic, intractable pain. In this chapter, we review our knowledge of the molecular mechanisms underlying vanilloid-induced neurotoxicity, which includes both TRPV1-mediated and independent signalling pathways.

Authors Ashutosh Kumar and Rakesh Kumar Majhi have equally contributed.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   549.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   549.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

CCK-B:

Cholecystokinin receptor-B

CGRP:

Calcitonin gene-related peptide

CNS:

Central nervous system

CTB:

Cholera toxin subunit B

DRG neuron:

Dorsal root ganglion neuron

ETC1:

Electron transport chain complex 1

ETC3:

Electron transport chain complex 3

ICK-peptides:

Inhibitory cystine knot peptides

ISH:

In situ hybridization

MPT:

Membrane permeability transition

NADA:

N-arachidonoyl-dopamine

NNOS:

Neuronal nitric oxide synthase

OLDA:

N-oleoyldopamine

PALDA:

N-palmitoyldopamine

PCR:

Polymerase chain reaction

PKC:

Protein kinase C

PMOR:

Plasma membrane NADH oxidoreductase

ROPA:

Resiniferonol 9,13,14-orthophenylacetate

ROS:

Reactive oxygen species

RTX:

Resiniferatoxin

SP:

Substance P

STEARDA:

N-stearoyldopamine

TG-neurons:

Trigeminal ganglion neurons

TiTX:

Tinyatoxin

TRPV1:

Transient receptor potential cation channel subfamily V member 1

References

  • Acs, G., Palkovits, M., & Blumberg, P. M. (1996). Specific binding of [3H]resiniferatoxin by human and rat preoptic area, locus ceruleus, medial hypothalamus, reticular formation and ventral thalamus membrane preparations. Life Sciences, 59, 1899–1908.

    CAS  PubMed  Google Scholar 

  • Aggarwal, B. B., & Shishodia, S. (2004). Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: Reasoning for seasoning. Annals of the New York Academy of Sciences, 1030, 434–441.

    CAS  PubMed  Google Scholar 

  • Amantini, C., Mosca, M., Lucciarini, R., Perfumi, M., Morrone, S., Piccoli, M., & Santoni, G. (2004). Distinct thymocyte subsets express the vanilloid receptor VR1 that mediates capsaicin-induced apoptotic cell death. Cell Death and Differentiation, 11, 1342–1356.

    CAS  PubMed  Google Scholar 

  • Andreev, Y. A., Kozlov, S. A., Koshelev, S. G., Ivanova, E. A., Monastyrnaya, M. M., Kozlovskaya, E. P., & Grishin, E. V. (2008). Analgesic compound from sea anemone Heteractis crispa is the first polypeptide inhibitor of vanilloid receptor 1 (TRPV1). The Journal of Biological Chemistry, 283, 23914–23921.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Appendino, G., & Szallasi, A. (1997). Euphorbium: Modern research on its active principle, resiniferatoxin, revives an ancient medicine. Life Sciences, 60, 681–696.

    CAS  PubMed  Google Scholar 

  • Aranda, F. J., Villalaín, J., & Gómez-Fernández, J. C. (1995). Capsaicin affects the structure and phase organization of phospholipid membranes. Biochimica et Biophysica Acta, 1234, 225–234.

    PubMed  Google Scholar 

  • Bates, B. D., Mitchell, K., Keller, J. M., Chan, C. C., Swaim, W. D., Yaskovich, R., Mannes, A. J., & Iadarola, M. J. (2010). Prolonged analgesic response of cornea to topical resiniferatoxin, a potent TRPV1 agonist. Pain, 149, 522–528.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bernardi, P. (1992). Modulation of the mitochondrial cyclosporin A-sensitive permeability transition pore by the proton electrochemical gradient. Evidence that the pore can be opened by membrane depolarization. The Journal of Biological Chemistry, 267, 8834–8839.

    CAS  PubMed  Google Scholar 

  • Bíró, T., Brodie, C., Modarres, S., Lewin, N. E., Acs, P., & Blumberg, P. M. (1998). Specific vanilloid responses in C6 rat glioma cells. Brain Research. Molecular Brain Research, 56, 89–98.

    PubMed  Google Scholar 

  • Bohlen, C. J., & Julius, D. (2012). Receptor-targeting mechanisms of pain-causing toxins: How ow? Toxicon, 60, 254–264.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bohlen, C. J., Priel, A., Zhou, S., King, D., Siemens, J., & Julius, D. (2010). A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain. Cell, 141, 834–845.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Brown, D. C., Iadarola, M. J., Perkowski, S. Z., Erin, H., Shofer, F., Laszlo, K. J., Olah, Z., & Mannes, A. J. (2005). Physiologic and antinociceptive effects of intrathecal resiniferatoxin in a canine bone cancer model. Anesthesiology, 103, 1052–1059.

    PubMed  Google Scholar 

  • Buck, S. H., & Burks, T. F. (1986). The neuropharmacology of capsaicin: Review of some recent observations. Pharmacological Reviews, 38, 179–226.

    CAS  PubMed  Google Scholar 

  • Burliński, P. J., Gonkowski, S., & Całka, J. (2011). Tetrodotoxin- and resiniferatoxin-induced changes in paracervical ganglion ChAT- and nNOS-IR neurons supplying the urinary bladder in female pigs. Acta Veterinaria Hungarica, 59, 455–463.

    PubMed  Google Scholar 

  • Cabeza-Arvelaiz, Y., & Schiestl, R. H. (2012). Transcriptome analysis of a rotenone model of parkinsonism reveals complex I-tied and -untied toxicity mechanisms common to neurodegenerative diseases. PloS One, 7, e44700.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D., & Julius, D. (1997). The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature, 389, 816–824.

    CAS  PubMed  Google Scholar 

  • Cavanaugh, D. J., Chesler, A. T., Jackson, A. C., Sigal, Y. M., Yamanaka, H., Grant, R., O’Donnell, D., Nicoll, R. A., Shah, N. M., Julius, D., & Basbaum, A. I. (2011). Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells. The Journal of Neuroscience, 31, 5067–5077.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chard, P. S., Bleakman, D., Savidge, J. R., & Miller, R. J. (1995). Capsaicin-induced neurotoxicity in cultured dorsal root ganglion neurons: Involvement of calcium-activated proteases. Neuroscience, 65, 1099–1108.

    CAS  PubMed  Google Scholar 

  • Chou, M. Z., Mtui, T., Gao, Y. D., Kohler, M., & Middleton, R. E. (2004). Resiniferatoxin binds to the capsaicin receptor (TRPV1) near the extracellular side of the S4 transmembrane domain. Biochemistry, 43, 2501–2511.

    CAS  PubMed  Google Scholar 

  • Chu, C. J., Huang, S. M., De Petrocellis, L., Bisogno, T., Ewing, S. A., Miller, J. D., Zipkin, R. E., Daddario, N., Appendino, G., Di Marzo, V., & Walker, J. M. (2003). N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia. The Journal of Biological Chemistry, 278, 13633–13639.

    CAS  PubMed  Google Scholar 

  • Chung, K., Klein, C. M., & Coggeshall, R. E. (1990). The receptive part of the primary afferent axon is most vulnerable to systemic capsaicin in adult rats. Brain Research, 511, 222–226.

    CAS  PubMed  Google Scholar 

  • Chung, W. Y., Jung, Y. J., Surh, Y. J., Lee, S. S., & Park, K. K. (2001). Antioxidative and antitumor promoting effects of [6]-paradol and its homologs. Mutation Research, 496, 199–206.

    CAS  PubMed  Google Scholar 

  • Cochereau, C., Sanchez, D., Bourhaoui, A., & Creppy, E. E. (1996). Capsaicin, a structural analog of tyrosine, inhibits the aminoacylation of tRNA(Tyr). Toxicology and Applied Pharmacology, 141, 133–137.

    CAS  PubMed  Google Scholar 

  • Cochereau, C., Sanchez, D., & Creppy, E. E. (1997). Tyrosine prevents capsaicin-induced protein synthesis inhibition in cultured cells. Toxicology, 117, 133–139.

    CAS  PubMed  Google Scholar 

  • Crompton, M. (1999). The mitochondrial permeability transition pore and its role in cell death. The Biochemical Journal, 341, 233–249.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cuypers, E., Yanagihara, A., Karlsson, E., & Tytgat, J. (2006). Jellyfish and other cnidarian envenomations cause pain by affecting TRPV1 channels. FEBS Letters, 580, 5728–5732.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Czaja, K., Burns, G. A., & Ritter, R. C. (2008). Capsaicin-induced neuronal death and proliferation of the primary sensory neurons located in the nodose ganglia of adult rats. Neuroscience, 154, 621–630.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dedov, V. N., Mandadi, S., Armati, P. J., & Verkhratsky, A. (2001). Capsaicin-induced depolarisation of mitochondria in dorsal root ganglion neurons is enhanced by vanilloid receptors. Neuroscience, 103, 219–226.

    CAS  PubMed  Google Scholar 

  • Docherty, R. J., Yeats, J. C., Bevan, S., & Boddeke, H. W. (1996). Inhibition of calcineurin inhibits the desensitization of capsaicin-evoked currents in cultured dorsal root ganglion neurones from adult rats. Pflügers Archiv, 431, 828–837.

    CAS  PubMed  Google Scholar 

  • Doyle, M. W., Bailey, T. W., Jin, Y. H., & Andresen, M. C. (2002). Vanilloid receptors presynaptically modulate cranial visceral afferent synaptic transmission in nucleus tractus solitarius. The Journal of Neuroscience, 22, 8222–8229.

    CAS  PubMed  Google Scholar 

  • Driedger, P. E., & Blumberg, P. M. (1980). Different biological targets for resiniferatoxin and phorbol 12 myristate 13-acetate. Cancer Research, 40, 1400–1404.

    CAS  PubMed  Google Scholar 

  • Escoubas, P., & Rash, L. (2004). Tarantulas: eight-legged pharmacists and combinatorial chemists. Toxicon, 43, 555–574.

    CAS  PubMed  Google Scholar 

  • Frey, M. R., Clark, J. A., Bateman, N. W., Kazanietz, M. G., Black, A. R., & Black, J. D. (2004). Cell cycle- and protein kinase C-specific effects of resiniferatoxin and resiniferonol 9,13,14-ortho-phenylacetate in intestinal epithelial cells. Biochemical Pharmacology, 67, 1873–1886.

    CAS  PubMed  Google Scholar 

  • Fry, B. G., Vidal, N., Norman, J. A., Vonk, F. J., Scheib, H., Ramjan, S. F., Kuruppu, S., Fung, K., Hedges, S. B., Richardson, M. K., Hodgson, W. C., Ignjatovic, V., Summerhayes, R., & Kochva, E. (2006). Early evolution of the venom system in lizards and snakes. Nature, 439, 584–588.

    CAS  PubMed  Google Scholar 

  • Garle, M. J., Knight, A., Downing, A. T., Jassi, K. L., Clothier, R. H., & Fry, J. R. (2000). Stimulation of dichlorofluorescin oxidation by capsaicin and analogues in RAW 264 monocyte/macrophages: Lack of involvement of the vanilloid receptor. Biochemical Pharmacology, 59, 563–572.

    CAS  PubMed  Google Scholar 

  • Gavva, N. R., Klionsky, L., Qu, Y., Shi, L., Tamir, R., Edenson, S., Zhang, T. J., Viswanadhan, V. N., Toth, A., Pearce, L. V., Vanderah, T. W., Porreca, F., Blumberg, P. M., Lile, J., Sun, Y., Wild, K., Louis, J. C., & Treanor, J. J. (2004). Molecular determinants of vanilloid sensitivity in TRPV1. The Journal of Biological Chemistry, 279, 20283–20295.

    CAS  PubMed  Google Scholar 

  • Goswami, C., Schmidt, H., & Hucho, F. (2007). TRPV1 at nerve endings regulates growth cone morphology and movement through cytoskeleton reorganization. The FEBS Journal, 274, 760–772.

    CAS  PubMed  Google Scholar 

  • Goswami, C., Rademacher, N., Smalla, K. H., Kalscheuer, V., Ropers, H. H., Gundelfinger, E. D., & Hucho, T. (2010). TRPV1 acts as a synaptic protein and regulates vesicle recycling. Journal of Cell Science, 123, 2045–2057.

    CAS  PubMed  Google Scholar 

  • Gracheva, E. O., Ingolia, N. T., Kelly, Y. M., Cordero-Morales, J. F., Hollopeter, G., Chesler, A. T., Sánchez, E. E., Perez, J. C., Weissman, J. S., & Julius, D. (2010). Molecular basis of infrared detection by snakes. Nature, 464, 1006–1011.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gracheva, E. O., Cordero-Morales, J. F., González-Carcacía, J. A., Ingolia, N. T., Manno, C., Aranguren, C. I., Weissman, J. S., & Julius, D. (2011). Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats. Nature, 476, 88–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Green, D. R., & Reed, J. C. (1998). Mitochondria and apoptosis. Science, 281, 1309–1312.

    CAS  PubMed  Google Scholar 

  • Hail, N., Jr., & Lotan, R. (2002). Examining the role of mitochondrial respiration in vanilloid-induced apoptosis. Journal of the National Cancer Institute, 94, 1281–1292.

    CAS  PubMed  Google Scholar 

  • Hail, N., Jr. (2003). Mechanisms of vanilloid-induced apoptosis. Apoptosis, 8, 251–262.

    CAS  PubMed  Google Scholar 

  • Holzer, P. (1991). Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacological Reviews, 43, 143–201.

    CAS  PubMed  Google Scholar 

  • Hoppe, U., Bergemann, J., Diembeck, W., Ennen, J., Gohla, S., Harris, I., Jacob, J., Kielholz, J., Mei, W., Pollet, D., Schachtschabel, D., Sauermann, G., Schreiner, V., Stäb, F., & Steckel, F. (1999). Coenzyme Q10, a cutaneous antioxidant and energizer. BioFactors, 9, 371–378.

    CAS  PubMed  Google Scholar 

  • Huang, M. T., Ma, W., Yen, P., Xie, J. G., Han, J., Frenkel, K., Grunberger, D., & Conney, A. H. (1997). Inhibitory effects of topical application of low doses of curcumin on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion and oxidized DNA bases in mouse epidermis. Carcinogenesis, 18, 83–88.

    CAS  PubMed  Google Scholar 

  • Huang, S. M., Bisogno, T., Trevisani, M., Al-Hayani, A., De Petrocellis, L., Fezza, F., Tognetto, M., Petros, T. J., Krey, J. F., Chu, C. J., Miller, J. D., Davies, S. N., Geppetti, P., Walker, J. M., & Di Marzo, V. (2002). An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proceedings of the National Academy of Sciences USA, 99, 8400–8405.

    CAS  Google Scholar 

  • Iida, T., Moriyama, T., Kobata, K., Morita, A., Murayama, N., Hashizume, S., Fushiki, T., Yazawa, S., Watanabe, T., & Tominaga, M. (2003). TRPV1 activation and induction of nociceptive response by a non-pungent capsaicin-like compound, capsiate. Neuropharmacology, 44, 958–967.

    CAS  PubMed  Google Scholar 

  • Inoue, K., Koizumi, S., Fuziwara, S., Denda, S., Inoue, K., & Denda, M. (2002). Functional vanilloid receptors in cultured normal human epidermal keratinocytes. Biochemical and Biophysical Research Communications, 291, 124–129.

    CAS  PubMed  Google Scholar 

  • Jancsó, N., & Jancsó, A. (1949). Desensitization of sensory nerve endings (in Hungarian). Kísérletes Orvostudomány, 2(Suppl), 15.

    Google Scholar 

  • Jancsó, G., & Király, E. (1981). Sensory neurotoxins: Chemically induced selective destruction of primary sensory neurons. Brain Research, 210, 83–89.

    PubMed  Google Scholar 

  • Jancsó, G., Kiraly, E., & Jancsó-Gábor, A. (1977). Pharmacologically induced selective degeneration of chemosensitive primary sensory neurones. Nature, 270, 741–743.

    PubMed  Google Scholar 

  • Jancsó, G., Karcsú, S., Király, E., Szebeni, A., Tóth, L., Bácsy, E., Joó, F., & Párducz, A. (1984). Neurotoxin induced nerve cell degeneration: Possible involvement of calcium. Brain Research, 295, 211–216.

    PubMed  Google Scholar 

  • Jancsó-Gábor, A., Szolcsányi, J., & Jancsó, N. (1970). Stimulation and desensitization of the hypothalamic heat-sensitive structures by capsaicin in rats. The Journal of Physiology, 208, 449–459.

    PubMed Central  PubMed  Google Scholar 

  • Jang, J. J., Kim, S. H., & Yun, T. K. (1989). Inhibitory effect of capsaicin on mouse lung tumor development. In Vivo, 3, 49–53.

    CAS  PubMed  Google Scholar 

  • Jiang, Y., Ruta, V., Chen, J., Lee, A., & MacKinnon, R. (2003). The principle of gating charge movement in a voltage-dependent K+ channel. Nature (London), 423, 42–48.

    CAS  Google Scholar 

  • Johnson, D. M., Garrett, E. M., Rutter, R., Bonnert, T. P., Gao, Y. D., Middleton, R. E., & Sutton, K. G. (2006). Functional mapping of the transient receptor potential vanilloid 1 intracellular binding site. Molecular Pharmacology, 70, 1005–1012.

    CAS  PubMed  Google Scholar 

  • Joó, F., Szolcsányi, J., & Jancsó-Gábor, A. (1969). Mitochondrial alterations in the spinal ganglion cells of the rat accompanying the long-lasting sensory disturbance induced by capsaicin. Life Sciences, 8, 621–626.

    PubMed  Google Scholar 

  • Jordt, S. E., & Julius, D. (2002). Molecular basis for species-specific sensitivity to “hot” chili peppers. Cell, 108, 421–430.

    CAS  PubMed  Google Scholar 

  • Jung, J., Hwang, S. W., Kwak, J., Lee, S. Y., Kang, C. J., Kim, W. B., Kim, D., & Oh, U. (1999). Capsaicin binds to the intracellular domain of the capsaicin-activated ion channel. The Journal of Neuroscience, 19, 529–538.

    CAS  PubMed  Google Scholar 

  • Jung, J., Lee, S. Y., Hwang, S. W., Cho, H., Shin, J., Kang, Y. S., Kim, S., & Oh, U. (2002). Agonist recognition sites in the cytosolic tails of vanilloid receptor 1. The Journal of Biological Chemistry, 277, 44448–44454.

    CAS  PubMed  Google Scholar 

  • Kang, H. J., Soh, Y., Kim, M. S., Lee, E. J., Surh, Y. J., Kim, H. R., Kim, S. H., & Moon, A. (2003). Roles of JNK-1 and p38 in selective induction of apoptosis by capsaicin in ras-transformed human breast epithelial cells. International Journal of Cancer, 103, 475–482.

    CAS  Google Scholar 

  • Karai, L., Brown, D. C., Mannes, A. J., Connelly, S. T., Brown, J., Gandal, M., Wellisch, O. M., Neubert, J. K., Olah, Z., & Iadarola, M. J. (2004). Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control. The Journal of Clinical Investigation, 113, 1344–1352.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kissin, I. (2008). Vanilloid-induced conduction analgesia: Selective, dose-dependent, long-lasting, with a low level of potential neurotoxicity. Anesthesia and Analgesia, 107, 271–281.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kitaguchi, T., & Swartz, K. J. (2005). An inhibitor of TRPV1 channels isolated from funnel Web spider venom. Biochemistry, 44, 15544–15549.

    CAS  PubMed  Google Scholar 

  • Knotkova, H., Pappagallo, M., & Szallasi, A. (2008). Capsaicin (TRPV1 Agonist) therapy for pain relief: Farewell or revival? The Clinical Journal of Pain, 24, 142–154.

    PubMed  Google Scholar 

  • Kostyuk, P., & Verkhratsky, A. (1994). Calcium stores in neurons and glia. Neuroscience, 63, 381–404.

    CAS  PubMed  Google Scholar 

  • Kroemer, G., & Reed, J. C. (2000). Mitochondrial control of cell death. Nature Medicine, 6, 513–519.

    CAS  PubMed  Google Scholar 

  • Kun, J., Helyes, Z., Perkecz, A., Bán, A., Polgár, B., Szolcsányi, J., & Pintér, E. (2012). Effect of surgical and chemical sensory denervation on non-neural expression of the Transient Receptor Potential Vanilloid 1 (TRPV1) receptors in the rat. Journal of Molecular Neuroscience, 48, 795–803.

    CAS  PubMed  Google Scholar 

  • Kuptniratsaikul, V., Thanakhumtorn, S., Chinswangwatanakul, P., Wattanamongkonsil, L., & Thamlikitkul, V. (2009). Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis. Journal of Alternative and Complementary Medicine, 15, 891–897.

    Google Scholar 

  • Kuzhikandathil, E. V., Wang, H., Szabo, T., Morozova, N., Blumberg, P. M., & Oxford, G. S. (2001). Functional analysis of capsaicin receptor (vanilloid receptor subtype 1) multimerization and agonist responsiveness using a dominant negative mutation. The Journal of Neuroscience, 21, 8697–8706.

    CAS  PubMed  Google Scholar 

  • Lee, E., & Surh, Y. J. (1998). Induction of apoptosis in HL-60 cells by pungent vanilloids, [6]-gingerol and [6]-paradol. Cancer Letters, 134, 163–168.

    CAS  PubMed  Google Scholar 

  • Lee, Y. S., Nam, D. H., & Kim, J. A. (2000). Induction of apoptosis by capsaicin in A172 human glioblastoma cells. Cancer Letters, 161, 121–130.

    CAS  PubMed  Google Scholar 

  • Lee, Y. S., Kang, Y. S., Lee, J. S., Nicolova, S., & Kim, J. A. (2004). Involvement of NADPH oxidase-mediated generation of reactive oxygen species in the apototic cell death by capsaicin in HepG2 human hepatoma cells. Free Radical Research, 38, 405–412.

    CAS  PubMed  Google Scholar 

  • Lee, Y. M., Li, W. H., Kim, Y. K., Kim, K. H., & Chung, J. H. (2008). Heat-induced MMP-1 expression is mediated by TRPV1 through PKCalpha signaling in HaCaT cells. Experimental Dermatology, 17, 864–870.

    CAS  PubMed  Google Scholar 

  • Li, W. H., Lee, Y. M., Kim, J. Y., Kang, S., Kim, S., Kim, K. H., Park, C. H., & Chung, J. H. (2007). Transient receptor potential vanilloid-1 mediates heat-shock-induced matrix metalloproteinase-1 expression in human epidermal keratinocytes. The Journal of Investigative Dermatology, 127, 2328–2335.

    CAS  PubMed  Google Scholar 

  • Limtrakul, P., Lipigorngoson, S., Namwong, O., Apisariyakul, A., & Dunn, F. W. (1997). Inhibitory effect of dietary curcumin on skin carcinogenesis in mice. Cancer Letters, 116, 197–203.

    CAS  PubMed  Google Scholar 

  • Littarru, G. P., & Tiano, L. (2007). Bioenergetic and antioxidant properties of coenzyme Q10: Recent developments. Molecular Biotechnology, 37, 31–37.

    CAS  PubMed  Google Scholar 

  • Luo, X. J., Peng, J., & Li, Y. J. (2011). Recent advances in the study on capsaicinoids and capsinoids. European Journal of Pharmacology, 650, 1–7.

    CAS  PubMed  Google Scholar 

  • Lynn, B., & Shakhanbeh, J. (1988). Substance P content of the skin, neurogenic inflammation and numbers of C-fibres following capsaicin application to a cutaneous nerve in the rabbit. Neuroscience, 24, 769–775.

    CAS  PubMed  Google Scholar 

  • Macho, A., Blázquez, M. V., Navas, P., & Muñoz, E. (1998). Induction of apoptosis by vanilloid compounds does not require de novo gene transcription and activator protein 1 activity. Cell Growth & Differentiation, 9, 277–286.

    CAS  Google Scholar 

  • Macho, A., Calzado, M. A., Muñoz-Blanco, J., Gómez-Díaz, C., Gajate, C., Mollinedo, F., Navas, P., & Muñoz, E. (1999). Selective induction of apoptosis by capsaicin in transformed cells: The role of reactive oxygen species and calcium. Cell Death and Differentiation, 6, 155–165.

    CAS  PubMed  Google Scholar 

  • Macho, A., Lucena, C., Calzado, M. A., Blanco, M., Donnay, I., Appendino, G., & Muñoz, E. (2000). Phorboid 20-homovanillates induce apoptosis through a VR1-independent mechanism. Chemistry & Biology, 7, 483–492.

    CAS  Google Scholar 

  • Maggi, C. A. (1991). Capsaicin and primary afferent neurons: From basic science to human therapy? Journal of the Autonomic Nervous System, 33, 1–14.

    CAS  PubMed  Google Scholar 

  • Marsch, R., Foeller, E., Rammes, G., Bunck, M., Kössl, M., Holsboer, F., Zieglgänsberger, W., Landgraf, R., Lutz, B., & Wotjak, C. T. (2007). Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. The Journal of Neuroscience, 27, 832–839.

    CAS  PubMed  Google Scholar 

  • McConkey, D. J., & Orrenius, S. (1996). The role of calcium in the regulation of apoptosis. Journal of Leukocyte Biology, 59, 775–783.

    CAS  PubMed  Google Scholar 

  • Micale, V., Cristino, L., Tamburella, A., Petrosino, S., Leggio, G. M., Di Marzo, V., & Drago, F. (2010). Enhanced cognitive performance of dopamine D3 receptor “knock-out” mice in the step-through passive-avoidance test: assessing the role of the endocannabinoid/endovanilloid systems. Pharmacological Research, 61, 531–536.

    CAS  PubMed  Google Scholar 

  • Miller, C. (1995). The charybdotoxin family of K+ channel-blocking peptides. Neuron, 15, 5–10.

    CAS  PubMed  Google Scholar 

  • 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. (2004). Capsaicin inhibits in vitro and in vivo angiogenesis. Cancer Research, 64, 644–651.

    CAS  PubMed  Google Scholar 

  • Morré, D. J., Chueh, P. J., & Morré, D. M. (1995). Capsaicin inhibits preferentially the NADH oxidase and growth of transformed cells in culture. Proceedings of the National Academy of Sciences USA, 92, 1831–1835.

    Google Scholar 

  • Morré, D. J., Sun, E., Geilen, C., Wu, L. Y., de Cabo, R., Krasagakis, K., Orfanos, C. E., & Morré, D. M. (1996). Capsaicin inhibits plasma membrane NADH oxidase and growth of human and mouse melanoma lines. European Journal of Cancer, 32A, 1995–2003.

    PubMed  Google Scholar 

  • Nagy, I., & Rang, H. (2000). Comparison of currents activated by noxious heat in rat and chicken primary sensory neurons. Regulatory Peptides, 96, 3–6.

    CAS  PubMed  Google Scholar 

  • Negri, L., Lattanzi, R., Giannini, E., Colucci, M., Margheriti, F., Melchiorri, P., Vellani, V., Tian, H., De Felice, M., & Porreca, F. (2006). Impaired nociception and inflammatory pain sensation in mice lacking the prokineticin receptor PKR1: Focus on interaction between PKR1 and the capsaicin receptor TRPV1 in pain behavior. The Journal of Neuroscience, 26, 6716–6727.

    CAS  PubMed  Google Scholar 

  • Neubert, J. K., Karai, L., Jun, J. H., Kim, H. S., Olah, Z., & Iadarola, M. J. (2003). Peripherally induced resiniferatoxin analgesia. Pain, 104, 219–228.

    CAS  PubMed  Google Scholar 

  • Neubert, J. K., Mannes, A. J., Karai, L. J., Jenkins, A. C., Zawatski, L., Abu-Asab, M., & Iadarola, M. J. (2008). Perineural resiniferatoxin selectively inhibits inflammatory hyperalgesia. Molecular Pain, 4, 03–13.

    Google Scholar 

  • O’Connell, P. J., Pingle, S. C., & Ahern, G. P. (2005). Dendritic cells do not transduce inflammatory stimuli via the capsaicin receptor TRPV1. FEBS Letters, 579, 5135–5139.

    PubMed  Google Scholar 

  • Otten, U., Lorez, H. P., & Businger, F. (1983). Nerve growth factor antagonizes the neurotoxic action of capsaicin on primary sensory neurones. Nature, 301, 515–517.

    CAS  PubMed  Google Scholar 

  • Pákáski, M., Hugyecz, M., Sántha, P., Jancsó, G., Bjelik, A., Domokos, A., Janka, Z., & Kálmán, J. (2009). Capsaicin promotes the amyloidogenic route of brain amyloid precursor protein processing. Neurochemistry International, 54, 426–430.

    PubMed  Google Scholar 

  • Pan, H. L., Khan, G. M., Alloway, K. D., & Chen, S. R. (2003). Resiniferatoxin induces paradoxical changes in thermal and mechanical sensitivities in rats: Mechanism of action. The Journal of Neuroscience, 23, 2911–2919.

    CAS  PubMed  Google Scholar 

  • Park, K. K., & Surh, Y. J. (1997). Effects of capsaicin on chemically-induced two-stage mouse skin carcinogenesis. Cancer Letters, 114, 183–184.

    CAS  PubMed  Google Scholar 

  • Pecze, L., Szabó, K., Széll, M., Jósvay, K., Kaszás, K., Kúsz, E., Letoha, T., Prorok, J., Koncz, I., Tóth, A., Kemény, L., Vizler, C., & Oláh, Z. (2008). Human keratinocytes are vanilloid resistant. PloS One, 3, e3419.

    PubMed Central  PubMed  Google Scholar 

  • Phillips, E., Reeve, A., Bevan, S., & McIntyre, P. (2004). Identification of species-specific determinants of the action of the antagonist capsazepine and the agonist PPAHV on TRPV1. The Journal of Biological Chemistry, 279, 17165–17172.

    CAS  PubMed  Google Scholar 

  • Pini, A., Baranowski, R., & Lynn, B. (1990). Long-term reduction in the number of C-Fibre Nociceptors following Capsaicin treatment of a cutaneous nerve in adult rats. The European Journal of Neuroscience, 2, 89–97.

    PubMed  Google Scholar 

  • Pórszász, R., Szolcsányi, J. (1991–1992). Circulatory and respiratory effects of capsaicin and resiniferatoxin on guinea pigs. Acta Biochimica Biophysica Hungarica, 26, 131–138.

    Google Scholar 

  • Pramanik, K. C., Boreddy, S. R., & Srivastava, S. K. (2011). Role of mitochondrial electron transport chain complexes in capsaicin mediated oxidative stress leading to apoptosis in pancreatic cancer cells. PloS One, 6, e20151.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Riera, C. E., Menozzi-Smarrito, C., Affolter, M., Michlig, S., Munari, C., Robert, F., Vogel, H., Simon, S. A., & le Coutre, J. (2009). Compounds from Sichuan and Melegueta peppers activate, covalently and non-covalently, TRPA1 and TRPV1 channels. British Journal of Pharmacology, 157, 1398–1409.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ritter, S., & Dinh, T. T. (1988). Capsaicin-induced neuronal degeneration: Silver impregnation of cell bodies, axons, and terminals in the central nervous system of the adult rat. The Journal of Comparative Neurology, 271, 79–90.

    CAS  PubMed  Google Scholar 

  • Roberts, J. C., Davis, J. B., & Benham, C. D. (2004). [3H]Resiniferatoxin autoradiography in the CNS of wild-type and TRPV1 null mice defines TRPV1 (VR-1) protein distribution. Brain Research, 995, 176–183.

    CAS  PubMed  Google Scholar 

  • Sardar, P., Kumar, A., Bhandari, A., & Goswami, C. (2012). Conservation of tubulin-binding sequences in TRPV1 throughout evolution. PloS One, 7, e31448.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sasamura, T., Sasaki, M., Tohda, C., & Kuraishi, Y. (1998). Existence of capsaicin-sensitive glutamatergic terminals in rat hypothalamus. Neuroreport, 9, 2045–2048.

    CAS  PubMed  Google Scholar 

  • Sculptoreanu, A., de Groat, W. C., Buffington, C. A., & Birder, L. A. (2005). Abnormal excitability in capsaicin-responsive DRG neurons from cats with feline interstitial cystitis. Experimental Neurology, 193, 437–443.

    PubMed  Google Scholar 

  • Shimomura, Y., Kawada, T., & Suzuki, M. (1989). Capsaicin and its analogs inhibit the activity of NADH-coenzyme Q oxidoreductase of the mitochondrial respiratory chain. Archives of Biochemistry and Biophysics, 270, 573–577.

    CAS  PubMed  Google Scholar 

  • Siemens, J., Zhou, S., Piskorowski, R., Nikai, T., Lumpkin, E. A., Basbaum, A. I., King, D., & Julius, D. (2006). Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature, 444, 208–212.

    CAS  PubMed  Google Scholar 

  • Southall, M. D., Li, T., Gharibova, L. S., Pei, Y., Nicol, G. D., & Travers, J. B. (2003). Activation of epidermal vanilloid receptor-1 induces release of proinflammatory mediators in human keratinocytes. The Journal of Pharmacology and Experimental Therapeutics, 304, 217–222.

    CAS  PubMed  Google Scholar 

  • Starowicz, K., Cristino, L., & Di Marzo, V. (2008). TRPV1 receptors in the central nervous system: Potential for previously unforeseen therapeutic applications. Current Pharmaceutical Design, 14, 42–54.

    CAS  PubMed  Google Scholar 

  • Sugimoto, T., Xiao, C., & Ichikawa, H. (1998). Neonatal primary neuronal death induced by capsaicin and axotomy involves an apoptotic mechanism. Brain Research, 807, 147–154.

    CAS  PubMed  Google Scholar 

  • Surh, Y. J. (2002). More than spice: Capsaicin in hot chili peppers makes tumor cells commit suicide. Journal of the National Cancer Institute, 94, 1263–1265.

    CAS  PubMed  Google Scholar 

  • Surh, Y. J., Lee, R. C., Park, K. K., Mayne, S. T., Liem, A., & Miller, J. A. (1995). Chemoprotective effects of capsaicin and diallyl sulfide against mutagenesis or tumorigenesis by vinyl carbamate and N-nitrosodimethylamine. Carcinogenesis, 16, 2467–2471.

    CAS  PubMed  Google Scholar 

  • Sutton, K. G., Garrett, E. M., Rutter, A. R., Bonnert, T. P., Jarolimek, W., & Seabrook, G. R. (2005). Functional characterisation of the S512Y mutant vanilloid human TRPV1 receptor. British Journal of Pharmacology, 146, 702–711.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Svichar, N., Kostyuk, P., & Verkhratsky, A. (1997). Mitochondria buffer Ca2+ entry but not intracellular Ca2+ release in mouse DRG neurones. Neuroreport, 8, 3929–3932.

    CAS  PubMed  Google Scholar 

  • Swarnkar, S., Singh, S., Goswami, P., Mathur, R., Patro, I. K., & Nath, C. (2012). Astrocyte activation: A key step in rotenone induced cytotoxicity and DNA damage. Neurochemical Research, 37, 2178–2189.

    CAS  PubMed  Google Scholar 

  • Szallasi, A., & Blumberg, P. M. (1999). Vanilloid (Capsaicin) receptors and mechanisms. Pharmacological Reviews, 51, 159–212.

    CAS  PubMed  Google Scholar 

  • Szallasi, A., Goso, C., Blumberg, P. M., & Manzini, S. (1993). Competitive inhibition by capsazepine of [3H]resiniferatoxin binding to central (spinal cord and dorsal root ganglia) and peripheral (urinary bladder and airways) vanilloid (capsaicin) receptors in the rat. The Journal of Pharmacology and Experimental Therapeutics, 267, 728–733.

    CAS  PubMed  Google Scholar 

  • Szallasi, A., Farkas-Szallasi, T., Tucker, J. B., Lundberg, J. M., Hökfelt, T., & Krause, J. E. (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 Research, 815, 177–184.

    CAS  PubMed  Google Scholar 

  • Szöke, E., Seress, L., & Szolcsányi, J. (1998). Reevaluation of the effect of neonatal capsaicin treatment on the basis of morphometrical studies. Neurobiology (Budapest, Hungary), 6, 477–478.

    Google Scholar 

  • Szöke, E., Seress, L., & Szolcsányi, J. (2002). Neonatal capsaicin treatment results in prolonged mitochondrial damage and delayed cell death of B cells in the rat trigeminal ganglia. Neuroscience, 113, 925–937.

    PubMed  Google Scholar 

  • Szolcsányi, J., Joó, F., & Jancsó-Gábor, A. (1971). Mitochondrial changes in preoptic neurons after capsaicin desensitization of the hypothalamic thermodetectors in rats. Nature, 229, 116–117.

    PubMed  Google Scholar 

  • Szolcsányi, J., Jancśo-Gábor, A., & Joo, F. (1975). Functional and fine structural characteristics of the sensory neuron blocking effect of capsaicin. Naunyn-Schmiedeberg's Archives of Pharmacology, 287, 157–169.

    PubMed  Google Scholar 

  • Tanaka, T., Kohno, H., Sakata, K., Yamada, Y., Hirose, Y., Sugie, S., & Mori, H. (2002). Modifying effects of dietary capsaicin and rotenone on 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis. Carcinogenesis, 23, 1361–1367.

    CAS  PubMed  Google Scholar 

  • Tender, G. C., Walbridge, S., Olah, Z., Karai, L., Iadarola, M., Oldfield, E. H., & Lonser, R. R. (2005). Selective ablation of nociceptive neurons for elimination of hyperalgesia and neurogenic inflammation. Journal of Neurosurgery, 102, 522–525.

    PubMed  Google Scholar 

  • Terlau, H., & Olivera, B. M. (2004). Conus venoms: A rich source of novel ion channel-targeted peptides. Physiological Reviews, 84, 41–68.

    CAS  PubMed  Google Scholar 

  • 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. (2010). Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway. Oncogene, 29, 285–296.

    CAS  PubMed  Google Scholar 

  • Tóth, A., Boczán, J., Kedei, N., Lizanecz, E., Bagi, Z., Papp, Z., Edes, I., Csiba, L., & Blumberg, P. M. (2005). Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain. Brain Research. Molecular Brain Research, 135, 162–168.

    PubMed  Google Scholar 

  • Tóth, B. I., Benko, S., Szöllosi, A. G., Kovács, L., Rajnavölgyi, E., & Bíró, T. (2009). Transient receptor potential vanilloid-1 signaling inhibits differentiation and activation of human dendritic cells. FEBS Letters, 583, 1619–1624.

    PubMed  Google Scholar 

  • Tsuchiya, H. (2001). Biphasic membrane effects of capsaicin, an active component in Capsicum species. Journal of Ethnopharmacology, 75, 295–299.

    CAS  PubMed  Google Scholar 

  • Valtschanoff, J. G., Rustioni, A., Guo, A., & Hwang, S. J. (2001). Vanilloid receptor VR1 is both presynaptic and postsynaptic in the superficial laminae of the rat dorsal horn. The Journal of Comparative Neurology, 436, 225–235.

    CAS  PubMed  Google Scholar 

  • Vellani, V., Colucci, M., Lattanzi, R., Giannini, E., Negri, L., Melchiorri, P., & McNaughton, P. A. (2006). Sensitization of transient receptor potential vanilloid 1 by the prokineticin receptor agonist Bv8. The Journal of Neuroscience, 26, 5109–5116.

    CAS  PubMed  Google Scholar 

  • Verkhratsky, A. J., & Petersen, O. H. (1998). Neuronal calcium stores. Cell Calcium, 24, 333–343.

    CAS  PubMed  Google Scholar 

  • Vlachova, V., Teisinger, J., Susankova, K., Lyfenko, A., Ettrich, R., & Vyklicky, L. (2003). Functional role of C-terminal cytoplasmic tail of rat vanilloid receptor 1. The Journal of Neuroscience, 23, 1340–1350.

    CAS  PubMed  Google Scholar 

  • Voets, T., Talavera, K., Owsianik, G., & Nilius, B. (2005). Sensing with TRP channels. Nature Chemical Biology, 1, 85–92.

    CAS  PubMed  Google Scholar 

  • Wardle, K. A., Furey, G., & Sanger, G. J. (1996). Pharmacological characterization of the vanilloid receptor in the rat isolated vas deferens. The Journal of Pharmacy and Pharmacology, 48, 285–291.

    CAS  PubMed  Google Scholar 

  • Welch, J. M., Simon, S. A., & Reinhart, P. H. (2000). The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat. Proceedings of the National Academy of Sciences USA, 97, 13889–13894.

    CAS  Google Scholar 

  • Winter, J. (1987). Characterization of capsaicin-sensitive neurones in adult rat dorsal root ganglion cultures. Neuroscience Letters, 80, 134–140.

    CAS  PubMed  Google Scholar 

  • Wolvetang, E. J., Larm, J. A., Moutsoulas, P., & Lawen, A. (1996). Apoptosis induced by inhibitors of the plasma membrane NADH-oxidase involves Bcl-2 and calcineurin. Cell Growth & Differentiation, 7, 1315–1325.

    CAS  Google Scholar 

  • Wong, R., Steenbergen, C., & Murphy, E. (2012). Mitochondrial permeability transition pore and calcium handling. Methods in Molecular Biology, 810, 235–242.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wood, J. N., Winter, J., James, I. F., Rang, H. P., Yeats, J., & Bevan, S. (1988). Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture. The Journal of Neuroscience, 8, 3208–3320.

    CAS  PubMed  Google Scholar 

  • Xu, X. J., Farkas-Szallasi, T., Lundberg, J. M., Hökfelt, T., Wiesenfeld-Hallin, Z., & Szallasi, A. (1997). Effects of the capsaicin analogue resiniferatoxin on spinal nociceptive mechanisms in the rat: behavioral, electrophysiological and in situ hybridization studies. Brain Research, 752, 52–60.

    CAS  PubMed  Google Scholar 

  • Yagi, T. (1990). Inhibition by capsaicin of NADH-quinone oxidoreductases is correlated with the presence of energy-coupling site 1 in various organisms. Archives of Biochemistry and Biophysics, 281, 305–311.

    CAS  PubMed  Google Scholar 

  • Zhu, S., Darbon, H., Dyason, K., Verdonck, F., & Tytgat, J. (2003). Evolutionary origin of inhibitor cystine knot peptides. The FASEB Journal, 17, 1765–1767.

    CAS  Google Scholar 

Download references

Acknowledgments

Funding from National Institute of Science Education and Research and Department of Biotechnology (Govt. India, grant number BT-BRB-TF-2-2011) is acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare existence of no competing interests.

Author information

Author notes

    Authors and Affiliations

    1. National Institute of Science Education and Research, Institute of Physics Campus, Sachivalaya Marg, Bhubaneswar, Orissa, India

      Ashutosh Kumar, Rakesh Kumar Majhi, Manoj Yadav & Chandan Goswami

    2. Monmouth Medical Center, Long Branch, NJ, USA

      Arpad Szallasi

    Authors
    1. Ashutosh Kumar
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Rakesh Kumar Majhi
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Manoj Yadav
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Arpad Szallasi
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Chandan Goswami
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Arpad Szallasi or Chandan Goswami .

    Editor information

    Editors and Affiliations

    1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee, USA

      Richard M. Kostrzewa

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2014 Springer Science+Business Media New York

    About this entry

    Cite this entry

    Kumar, A., Majhi, R.K., Yadav, M., Szallasi, A., Goswami, C. (2014). TRPV1 Activators (“Vanilloids”) as Neurotoxins. In: Kostrzewa, R. (eds) Handbook of Neurotoxicity. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5836-4_94

    Download citation

    Publish with us

    Policies and ethics

    Search

    Navigation