Skip to main content
SpringerLink
Log in

Capsaicin and Sensory Neurones: A Historical Perspective

  • Chapter
  • First Online:
Capsaicin as a Therapeutic Molecule

Part of the book series: Progress in Drug Research ((PDR,volume 68))

Abstract

Capsaicin, the pungent ingredient of red pepper has become not only a “hot” topic in neuroscience but its new target-related unique actions have opened the door for the drug industry to introduce a new chapter of analgesics. After several lines of translational efforts with over 1,000 patents and clinical trials, the 8 % capsaicin dermal patch reached the market and its long-lasting local analgesic effect in some severe neuropathic pain states is now well established. This introductory chapter outlines on one hand the historical background based on the author’s 50 years of experience in this field and on the other hand emphasizes new scopes, fascinating perspectives in pharmaco-physiology, and molecular pharmacology of nociceptive sensory neurons. Evidence for the effect of capsaicin on C-polymodal nociceptors (CMH), C-mechanoinsensitive (CHMi), and silent C-nociceptors are listed and the features of the capsaicin-induced blocking effects of nociceptors are demonstrated. Common and different characteristics of nociceptor-blocking actions after systemic, perineural, local, intrathecal, and in vitro treatments are summarized. Evidence for the misleading conclusions drawn from neonatal capsaicin pretreatment is presented. Perspectives opened from cloning the capsaicin receptor “Transient Receptor Potential Vanilloid 1’’ (TRPV1) are outlined and potential molecular mechanisms behind the long-lasting functional, ultrastructural, and nerve terminal-damaging effects of capsaicin and other TRPV1 agonists are summarized. Neurogenic inflammation and the long-list of “capsaicin-sensitive” tissue responses are mediated by an unorthodox dual sensory-efferent function of peptidergic TRPV1-expressing nerve terminals which differ from the classical efferent and sensory nerve endings that have a unidirectional role in neuroregulation. Thermoregulatory effects of capsaicin are discussed in detail. It is suggested that since hyperthermia and burn risk due to enhanced noxious heat threshold are the major obstacles of some TRPV1 antagonists, they could be overcome. The special “multisteric” gating function of the TRPV1 cation channel provides the structural ground for blocking chemical activation of TRPV1 without affecting its responsiveness to physical stimuli. A new chapter of potential analgesics targeting nociceptors is now already supported for pain relief in persistent pathological pain states.

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

Access this chapter

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 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
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

Institutional subscriptions

References

  • Abelli L, Geppetti P, Maggi CA (1993) Relative contribution of sympathetic and sensory nerves to thermal nociception and tissue trophism in rats. Neuroscience 57:739–745

    CAS  PubMed  Google Scholar 

  • Akagi H, Konishi S, Otsuka M, Yanagisava M (1985) The role of substance P as a neurotransmitter in the reflexes of slow time courses in the neonatal rat spinal cord. Br J Pharmacol 84:663–673

    CAS  PubMed Central  PubMed  Google Scholar 

  • Andresen T, Staahl C, Oksche A, Mansikka H, Arendt-Nielsen L, Drewes AM (2011) Effect of transdermal opioids in experimentally induced superficial, deep and hyperalgesic pain. Br J Pharmacol 164:934–945

    CAS  PubMed Central  PubMed  Google Scholar 

  • Baccaglini PJ, Hogan PG (1983) Some rat sensory neurons in culture express characteristics of differentiated pain sensory cells. Proc Natl Acad Sci 80:594–598

    CAS  PubMed Central  PubMed  Google Scholar 

  • Baez-Nieto D, Castillo JP, Dragicevic C, Alvarez O, Latorre R (2011) Thermo-TRP channels: biophysics of polymodal receptors. In: Islam MS (ed) Transient receptor potential channels. Advances in experimental medicine and biology. Springer, Berlin

    Google Scholar 

  • Banke TG (2011) The dilated TRPA1 channel pore state is blocked by amiloride and analogues. Brain Res 1381:21–30

    CAS  PubMed  Google Scholar 

  • Barthó L, Szolcsányi J (1978) The site of action of capsaicin on the guinea-pig isolated ileum. Naunyn-Schmiedeberg’s Arch Pharmacol 305:75–81

    Google Scholar 

  • Barthó L, Stein C, Herz A (1990) Involvement of capsaicin-sensitive neurons in hyperalgesia and enhanced opioid antinociception in inflammation. Naunyn-Schmiedeberg’s Arch Pharmacol 342:666–670

    Google Scholar 

  • Bauman TK, Simone DA, Shain CN, LaMotte RH (1991) Neurogenic hyperalgesia the search for the primary cutaneous affeent fibers that contribute to capsaicin-induced pain and hyperalgesia. J Neurophysiol 66:212–227

    Google Scholar 

  • Bayliss WM (1901) On the origin from the spinal cord of vaso-dilator fibres of the hindlimb and on the nature of these fibres. J Physiol 26:173–209

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bessou P, Perl ER (1969) Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli. J Neurophysiol 32:1025–1043

    CAS  PubMed  Google Scholar 

  • Bevan S, Docherty RJ (1993) Cellular mechanisms of the action of capsaicin. In: Wood JN (ed) Capsaicin in the study of pain. Academic Press, New York, pp 27–44

    Google Scholar 

  • Bevan S, Szolcsányi J (1990) Sensory neuron-specific actions of capsaicin: mechanisms and applications. Trends Pharmacol Sci 11:330–333

    CAS  PubMed  Google Scholar 

  • Binshtok AM, Bean BP, Woolf CJ (2007) Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 449:607–610

    CAS  PubMed  Google Scholar 

  • Bölcskei K, Tékus V, Dézsi L, Szolcsányi J, Pethő G (2010) Antinociceptive desensitizing actions of TRPV1 receptor agonists capsaicin, resiniferatoxin and N-oleoyldopamine as measured by determination of the noxious heat and cold thresholds in the rat. Eur J Pain 14:480–486

    PubMed  Google Scholar 

  • Boulant JA (2006) Neuronal basis of Hammel’s model for set-point thermoregulation. J Appl Physiol 100:1347–1350

    PubMed  Google Scholar 

  • Browning KN, Babic T, Holmes GM, Swartz E, Travagli RA (2013) A critical re-evaluation of the specificity of action of perivagal capsaicin. J Physiol 591:1563–1580

    PubMed Central  PubMed  Google Scholar 

  • Buck SH, Burks TF (1986) The neuropharmacology of capsaicin: a review of some recent observations. Pharmacol Rev 38:179–226

    CAS  PubMed  Google Scholar 

  • Buck SH, Deskmukh PP, Yamamura HI, Burks TF (1981) Thermal analgesia and substance P depletion induced by capsaicin in guinea-pigs. Neuroscience 6:2217–2222

    CAS  PubMed  Google Scholar 

  • Cao E, Cordero-Morales JF, Liu B, Qin F, Julius D (2013) TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids. Neuron 77:667–679

    CAS  PubMed Central  PubMed  Google Scholar 

  • Caterina MJ (2007) Transient receptor potential ion channels as participants in thermosensation and thermoregulation. Am J Physiol Regul Integr Comp Physiol 292:R64–R76

    CAS  PubMed  Google Scholar 

  • 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 389:816–824

    CAS  PubMed  Google Scholar 

  • Cavanaugh DJ, Chesler AT, Jackson AC, Sigal YM, Yamanaka H, Grant R, O’Donnell D, Nicoll RA, Shah NM, Julius D, Basbaum AI (2011) Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells. J Neurosci 31:5067–5077

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cervero F, McRitchie HA (1981) Neonatal capsaicin and thermal nociception: a paradox. Brain Res 215:414–418

    CAS  PubMed  Google Scholar 

  • Chiba T, Masuko S, Kavano H (1986) Correlation of mitochondrial swelling after capsaicin treatment and substance P and somatostatin immunoreactivity in small neurons of dorsal root ganglion in the rat. Neurosci Lett 64:311–316

    CAS  PubMed  Google Scholar 

  • Chiu IM, von Hehn CA, Woolf CJ (2012) Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat Neurosci 15:1063–1067

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chung K, Schwen RJ, Coggeshall RE (1985) Ureteral axon damage following subcutaneous administration of capsaicin in adult rats. Neurosci Lett 53:221–226

    CAS  PubMed  Google Scholar 

  • Chung K, Klein CM, Coggeshall RE (1990) The receptive part of the primary afferent axon is most vulnerable to systemic capsaicin in adult rats. Brain Res 511:222–226

    CAS  PubMed  Google Scholar 

  • Chung MK, Güler AD, Caterina MJ (2008) TRPV1 shows dynamic ionic selectivity during agonist stimulation. Nat Neurosci 11:555–564

    CAS  PubMed  Google Scholar 

  • Clapham DE, Miller C (2011) A thermodynamic framework for understanding temperature sensing by transient receptor potential (TRP) channels. Proc Natl Acad Sci 108:19492–19497

    CAS  PubMed Central  PubMed  Google Scholar 

  • De Vries DJ, Blumberg PM (1989) Thermoregulatory effects of resiniferatoxin in the mouse: comparison with capsaicin. Life Sci 44:711–715

    PubMed  Google Scholar 

  • Derry S, Moore RA (2012) Topical capsaicin (low concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev 9:CD010111

    Google Scholar 

  • Derry S, Sven-Rice A, Cole P, Tan T, Moore RA (2013) Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev. doi:10.1002/14651858.CD007393.pub3

    Google Scholar 

  • Dickenson A, Hughes C, Fueff A, Dray A (1990) A spinal mechanism of action is involved in the antinociception produced by the capsaicin analogue NE 19550 (olvanil). Pain 43:353–362

    CAS  PubMed  Google Scholar 

  • Du Mez AG (1917) A century of the United States Pharmacopoeia (1820–1920). Ph.D. Thesis, University of Wisconsin cf. Capsaicin Wikipedia, the free encyclopedia

    Google Scholar 

  • Dux M, Sann H, Schemann M, Jancsó G (1999) Changes in fibre populations of the rat hairy skin following selective chemodenervation by capsaicin. Cell Tissue Res 296:471–477

    CAS  PubMed  Google Scholar 

  • Foster RW, Ramage AG (1981) The action of some chemical irritants on somatosensory receptors of the cat. Neuropharmacology 20:191–198

    CAS  PubMed  Google Scholar 

  • Fr-K Pierau, Szolcsányi J (1989) Neurogenic inflammation; axon reflex in pigs. Agents Actions 26:231–232

    Google Scholar 

  • Fr-K Pierau, Szolcsányi J, Sann H (1986) The effect of capsaicin on afferent nerves and temperature regulation of mammals and birds. J Therm Biol 11:95–100

    Google Scholar 

  • Gamse R (1982) Capsaicin and nociception in the rat and mouse: possible role of substance P. Naunyn-Schmiedeberg’s Arch Pharmacol 320:205–216

    CAS  Google Scholar 

  • Garami A, Almeida MC, Nucci TB, Hew-Butler T, Soriano RN, Pakai E, Nakamura K, Morrison SF, Romanovsky AA (2010) The TRPV1 channel in normal thermoregulation: what thave we learned from experiments using different tools? In: Gomtsyan A, Faltynek CR (eds) Vanilloid receptor TRPV1 in drug discovery. Wiley, Hoboken, pp 351–402

    Google Scholar 

  • Garami A, Pakai E, Oliveira DL, Steiner AA, Wanner SP, Almeida MC, Lesnikov VA, Gavva NR, Romanovsky AA (2011) Thermoregulatory phenotype of the Trpv1 knockout mouse: thermoeffector dysbalance with hyperkinesis. J Neurosci 31:1721–1733

    CAS  PubMed Central  PubMed  Google Scholar 

  • Geissler E, Moeller J (1887) Real-Encyclopadie der gesamten Pharmacie, vol 2. Urban and Co, Leipzig

    Google Scholar 

  • Guenther S, Reeh PW, Kress M (1999) Rises in [Ca2+]i mediate capsaicin- and proton-induced heat sensitization of rat primary nociceptive neurons. Eur J Neurosci 11:3143–3150

    CAS  PubMed  Google Scholar 

  • Gunthorpe MJ, Chizh BA (2012) Clinical development of TRPV1 antagonists: targeting a pivotal point in the pain pathway. Drug Discov Today 14:56–57

    Google Scholar 

  • Hamalainen MM, Subieta A, Arpey C, Brennan TJ (2009) Differential effect of capsaicin treatment of pain-related behaviors after plantar incision. J Pain 10:637–645

    CAS  PubMed Central  PubMed  Google Scholar 

  • Han L, Ma C, Liu Q, Weng HJ, Cui Y, Tang Z, Kim Y, Nie H, Qu L, Patel KN, Li Z, McNeil B, He S, Guan Y, Xiao B, LaMotte RH, Dong X (2013) A subpopulation of nociceptors specifically linked to itch. Nat Neurosci 16:174–182

    CAS  PubMed Central  PubMed  Google Scholar 

  • Heyman I, Rang HP (1985) Depolarizing responses to capsaicin in a subpopulation of rat dorsal root ganglion cells. Neurosci Lett 56:69–75

    CAS  PubMed  Google Scholar 

  • Hőgyes A (1878) Beitrage zur physiologischen Wirkung der Bestandteile des Capsicum annuum. Arch Exp Pathol Pharmakol 9:117–130

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Holzer P (2007) Role of visceral afferent neurons in mucosal inflammation and defense. Curr Opin Pharmacol 7:563–569

    CAS  PubMed  Google Scholar 

  • Holzer P, Sametz W (1986) Gastric mucosal protection against ulcerogenic factors in the rat mediated by capsaicin-sensitive afferent neurons. Gastroenterology 91:975–981

    CAS  PubMed  Google Scholar 

  • Hori T (1981) Thermosensitivity of preoptic and anterior hypothalamic neurons in the capsaicin-desensitized rat. Pfügers Arch 389:297–299

    CAS  Google Scholar 

  • Hori T (1984) Capsaicin and central control of thermoregulation. Pharm Ther 26:389–416

    CAS  Google Scholar 

  • Huang J, Zhang X, McNaughton PA (2006) Inflammatory pain: the cellular basis of heat hyperalgesia. Curr Neuropharmacol 4:197–206

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jancsó N (1955) Speicherung Stoffanreicherung im Retikuloendothel und in der Niere. Akadémiai Kiadó, Budapest

    Google Scholar 

  • Jancsó N (1964) Neurogenic inflammatory response. Acta Physiol Hung Suppl 24:3–4

    Google Scholar 

  • Jancsó N (the late), Jancsó-Gábor A, Szolcsányi J (1967) Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Br J Pharmacol 31:138–151

    Google Scholar 

  • Jancsó N (the late), Jancsó-Gábor A, Szolcsányi J (1968) The role of sensory nerve endings in neurogenic inflammation induced in human skin and in the eye and paw of the rat. Br J Pharmac 33:32–41

    Google Scholar 

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

    PubMed  Google Scholar 

  • Jancsó G, Király E, Jancsó-Gábor A (1980) Direct evidence for an axonal site of action of capsaicin. Naunyn Schmiedebergs Arch Pharmacol 313:91–94

    PubMed  Google Scholar 

  • Jancsó G, Király E, Such G, Joó F, Nagy A (1987) Neurotoxic effect of capsaicin in mammals. Acta Physiol Hung 69:295–313

    PubMed  Google Scholar 

  • Jancsó-Gábor A, Szolcsányi J (1972) Neurogenic inflammatory responses. J Dental Res 41:264–269

    Google Scholar 

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

    PubMed Central  PubMed  Google Scholar 

  • Jancsó-Gábor A, Szolcsányi J, Jancsó N (1970b) Irreversible impairment of thermoregulation induced by capsaicin and similar pungent substances in rats and guinea-pigs. J Physiol 206:495–507

    PubMed Central  PubMed  Google Scholar 

  • Jessell TM, Iversen LL, Cuello AC (1978) Capsaicin-induced depletion of substance P from primary sensory neurones. Brain Res 152:183–188

    CAS  PubMed  Google Scholar 

  • Jhamandas K, Yaksh TL, Harty G, Szolcsányi J, Go VL (1984) Action of intrathecal capsaicin and its structural analogues on the content and release of spinal substance P: selectivity of action and relationship to analgesia. Brain Res 306:215–225

    CAS  PubMed  Google Scholar 

  • Johanek LM, Meyer RA, Friedman RM, Greenquist KW, Shim B, Borzan J, Hartke T, LaMotte RH, Ringkamp M (2008) A role for polymodal C-fiber afferents in nonhistaminergic itch. J Neurosci 28:7659–7669

    CAS  PubMed Central  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 Sci 8:621–626

    PubMed  Google Scholar 

  • Kauer JA, Gibson HE (2009) Hot flash: TRPV channels in the brain. Trends Neurosci 32:215–224

    CAS  PubMed  Google Scholar 

  • Kenins P (1982) Responses of single nerve fibres to capsaicin applied to the skin. Neurosci Lett 29:83–88

    CAS  PubMed  Google Scholar 

  • Kim H, Cui L, Kim J, Kim SJ (2009) Transient receptor potential vanilloid type 1 receptor regulates glutamatergic synaptic inputs to the spinothalamic tract neurons of the spinal cord deep dorsal horn. Neuroscience 160:508–516

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kleggetveit IP, Namer B, Schmidt R, Helas T, Rückel M, Orstavik K, Schmelz M, Jorum E (2012) High spontaneous activity of C-nociceptors in painful polyneuropathy. Pain 153:2040–2047

    CAS  PubMed  Google Scholar 

  • Konietzny F, Hensel H (1983) The effect of capsaicin on the response characteristics of human C-polymodal nociceptors. J Therm Biol 8:213–215

    CAS  Google Scholar 

  • Kort ME, Kym PR (2012) TRPV1 antagonists: clinical setbacks and prospects for future development. Prog Med Chem 51:57–70

    CAS  PubMed  Google Scholar 

  • LaMotte RH, Shain CN, Simone DA, Tsai EF (1991) Neurogenic hyperalgesia: psychophysical studies of undrlying mehcanisms. J Neurophysiol 66:190–211

    CAS  PubMed  Google Scholar 

  • LaMotte RH, Lundberg LE, Torebjörk HE (1992) Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin. J Physiol 448:749–764

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lawson SN, Harper AA (1984) Neonatal capsaicin is not a specific neurotoxin for sensory C-fibres or small dark cells of rat dorsal root ganglia. In: Chahl LA, Szolcsányi J, Lembeck F (eds) Antidromic Vasodilatation and Neurogenic Inflammation. Akadémiai Kiadó, Budapest, pp 111–116

    Google Scholar 

  • Lee TS (1954) Physiological gustatory sweating in a warm climate. J Physiol 124:528–542

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lembeck F (1987) Columbus, capsicum and capsaicin: past, present and future. Acta Physiol Hung 69:263–273

    Google Scholar 

  • Lewis T (1927) The blood vessels of the human skin and their responses. Shaw, London

    Google Scholar 

  • Lewis T (1937) The nocifensor system of nerves and its reactions. Br Med J 194:431–435

    Google Scholar 

  • Lundberg JM (1996) Pharmacology of cotransmission in the autonomic nervous system: integrative aspects on amines, neuropeptides, adenosin triphosphate, amino acids and nitric oxid. Pharmacol Rev 48:113–178

    CAS  PubMed  Google Scholar 

  • Lynn B, Schütterle S, Pierau Fr-K (1996) The vasodilator component of neurogenic inflammation is caused by a special subclass of heat-sensitive nociceptors in the skin of the pig. J Physiol 494:587–593

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mac Neish RS (1964) Ancient mesoamerican civilization. Science 143:531–553

    CAS  Google Scholar 

  • Maggi CA (1995) Tachykinins and calcitonin gene-related peptide (CGRP) as co-transmitters released from peripheral endings of sensory nerves. Prog Neurobiol 45:1–98

    CAS  PubMed  Google Scholar 

  • Maggi CA, Borsini F, Santicioli P, Geppetti P, Abelli L, Evangelista S, Manzini S, Theodorsson-Norheim E, Somma V, Amenta F (1987) Cutaneous lesions in capsaicin-pretreated rats. A trophic role of capsaicin-sensitive afferents? Naunyn Schmiedebergs Arch Pharmacol 336:538–545

    CAS  PubMed  Google Scholar 

  • Maggi CA, Patacchini R, Giuliani S, Santicioli P, Meli A (1988) Evidence for two independent modes of activation of the “efferent” function of capsaicin-sensitive nerves. Eur J Pharmacol 156:367–373

    CAS  PubMed  Google Scholar 

  • Majno G, Palade GE, Schoefl GS (1961) Studies on inflammation. II. The site of action of histamine and serotonin along the vascular tree: a topographic study. J Biophys Biochem Cytol 11:607–626

    CAS  PubMed Central  PubMed  Google Scholar 

  • Makara GB, Stark E, Mihály K (1967) Sites at which formalin and capsaicin act to stimulate corticotropin secretion. Can J Physiol Pharmacol 45:669–674

    CAS  PubMed  Google Scholar 

  • Marsh SJ, Stansfeld CE, Brown DA, Davey R, McCarthy D (1987) The mechanism of action of capsaicin on sensory C-type neurons and their axon in vitro. Neuroscience 23:275–290

    CAS  PubMed  Google Scholar 

  • Martin HA, Basbaum AJ, Kwiat GC, Goetzl EJ, Levine JD (1987) Leukotriene and prostaglandin sensitization of cutaneous high-threshold C- and A-delta mechanoreceptors in the hairy skin of rat hindlimbs. Neurosci 22:651–659

    CAS  Google Scholar 

  • McDonald DM (1988) Neurogenic inflammation in the rat trachea I. Changes in venules, leucocytes and epithelial cells. J Neurocytol 17:583–603

    CAS  PubMed  Google Scholar 

  • Melzack R, Wall PD (1965) Pain mechanisms: a new theory. Science 150:971–979

    CAS  PubMed  Google Scholar 

  • Micevych PE, Yaksh TL, Szolcsányi J (1983) Effect of intrathecal capsaicin analogues on the immunofluorescence of peptides and serotonin in the dorsal horn in rats. Neuroscience 8:123–131

    CAS  PubMed  Google Scholar 

  • Molnár J (1965) Pharmacologic effect of capsaicin the sharp tasting principle in paprika (in German). Arzneimittel Forschung 15:718–727

    PubMed  Google Scholar 

  • Montell C (2011) The history of TRP channels, a commentary and reflection. Pfügers Arch 461:499–506

    CAS  Google Scholar 

  • Morrison SF, Nakamura K (2011) Central neural pathways for thermoregulation. Front Biosci 16:74–104

    CAS  Google Scholar 

  • Mózsik Gy, Dömötör A, Past T, Vas V, Perjési P, Kuzma M, Blázich Gy, Szolcsányi J (2009) Capsaicinoids from the plant cultivation to the production of the human medical drug. Akadémiai Kiadó, Budapest

    Google Scholar 

  • Nagy JI, Iversen LL, Goedert M, Chapman D, Hunt SP (1983) Dose-dependent effects of capsaicin on primary sensory neurons in the neonatal rat. J Neurosci 3:399–406

    CAS  PubMed  Google Scholar 

  • Nelson EK (1919) The constitution of capsaicin, the pungent principle of capsicum. J Am Chem Soc 41:1115–1121

    CAS  Google Scholar 

  • Németh J, Zs Helyes, Oroszi G, Jakab B, Pintér E, Szilvássy Z, Szolcsányi J (2003) Role of voltage-gated cation channels and axon reflexes in the release of sensory neuropeptides by capsaicin from isolated rat trachea. Eur J Pharmacol 458:313–318

    PubMed  Google Scholar 

  • Nilius B, Owsianik G (2011) The transient receptor potential family of ion channels. Genome Biol 12:218–228

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nothnagel H (1870) Handbuch der Arzneimittellehre. Hirschwald A Verlag, Berlin

    Google Scholar 

  • Palazzo E, Rossi F, Maione S (2008) Role of TRPV1 receptors in descending modulation of pain. Mol Cell Endocrinol 286:S79–S83

    CAS  PubMed  Google Scholar 

  • Palermo NN, Brown HK, Smith DL (1981) Selective neurotoxic action of capsaicin on glomerular C-type terminals in rat substantia gelatinosa. Brain Res 208:506–510

    CAS  PubMed  Google Scholar 

  • Pan YZ, Pan HL (2004) Primary afferent stimulation differentially potentiates excitatory and inhibitory inputs to spinal lamina II outer and inner neurons. 91:2413–2421

    Google Scholar 

  • Pethő G, Szolcsányi J (1996) Excitation of central and peripheral terminals of primary afferent neurons by capsaicin in vivo. Life Sci 58:47–53

    Google Scholar 

  • Petsche U, Fleischer E, Lembeck F, Handwerker HO (1983) The effect of capsaicin application to a peripheral nerve on impulse conduction in functionally identified afferent nerve fibres. Brain Res 265:233–240

    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. Eur J Neurosci 2:89–97

    PubMed  Google Scholar 

  • Pintér E, Szolcsányi J (1995) Plasma extravasation in the skin and pelvic organs evoked by antidromic stimulation of the lumbosacral dorsal roots of the rat. Neuroscience 68:603–614

    PubMed  Google Scholar 

  • Pintér E, Zs Helyes, Szolcsányi J (2006) Inhibitory effect of somatostatin on inflammation and nociception. Pharmacol Ther 112:440–456

    PubMed  Google Scholar 

  • Planells-Cases R, Valente P, Ferrer-Montiel A, Qin F, Szállási Á (2011) Complex regulation of TRPV1 and related thermo-TRPs: implications for therapeutic intervention. Adv Exp Med Biol 704:491–515

    CAS  PubMed  Google Scholar 

  • Pórszász R, Szolcsányi J (1994) Antidromic vasodilatation in the striated muscle and its sensitivity to resiniferatoxin in the rat. Neurosci Lett 182:267–270

    PubMed  Google Scholar 

  • Romanovsky AA, Almeida MC, Garami A, Steiner AA, Norman MH, Morrison SF, Nakamura K, Burmeister JJ, Nucci TB (2009) The transient receptor potential vanilloid-1 channel in thermoregulation: a thermosensor it is not. Pharmacol Rev 61:228–261

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rukwied R, Dush M, Schley M, Forsh E, Schmelz M (2008) Nociceptor sensitization to mechanical and thermal stimuli in pig skin in vivo. Eur J Pain 12:242–250

    PubMed  Google Scholar 

  • Satinoff E (1978) Neural organization and evolution of thermal regulation in mammals. Science 201:16–22

    CAS  PubMed  Google Scholar 

  • Schmelz M, Schmidt R, Ringkamp M, Handwerker HO, Torebjörk HE (1994) Sensitization of insensitive branches of C nociceptors in human skin. J Physiol 480:389–394

    CAS  PubMed Central  PubMed  Google Scholar 

  • Schmelz M, Schmidt R, Handwerker HO, Torebjörk HE (2000a) Enconding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibres. Brain 3:560–571

    Google Scholar 

  • Schmelz M, Michael K, Weidner C, Schmidt R, Torebjörk HE, Handwerker HO (2000b) Which nerve fibers mediate the axon reflex flare in human skin. NeuroReport 11:645–648

    CAS  PubMed  Google Scholar 

  • Schmidt R, Schmelz M, Torebjörk HE, Handwerker HO (2000) Mechano-insensitive nociceptors encode pain evoked by tonic pressure to human skin 98:793–800

    CAS  Google Scholar 

  • Seno N, Dray A (1993) Capsaicin-induced activation of fine afferent fibres from rat skin in vitro. Neuroscience 55:563–569

    CAS  PubMed  Google Scholar 

  • Sherrington CS (1906) The integrative action of the nervous system. Scribner, New York

    Google Scholar 

  • Steenland HVV, Ko SW, Wu LJ, Zhuo M (2006) Hot receptors in the brain. Mol Pain 8:2–34

    Google Scholar 

  • Suzuki T, Iwai K (1984) Constituents of red pepper species: chemistry, biochemistry, pharmacology and food science of the pungent principle of Capsicum species. In: Brossi A (ed) The alkaloids, vol 23. Academic Press, Orlando, pp 227–299

    Google Scholar 

  • Szállási Á, Blumberg PM (1989) Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper. Neuroscience 30:515–520

    PubMed  Google Scholar 

  • Szállási Á, Blumberg PM (1990) Specific binding of resiniferatoxin, an ultrapotent capsaicin analog, by dorsal root ganglion membranes. Brain Res 524:106–111

    PubMed  Google Scholar 

  • Szállási Á, Blumberg PM (1999) Vanilloid (capsaicin) receptors and mechanism. Pharmacol Rev 51:159–211

    PubMed  Google Scholar 

  • Szelényi Z, Hummel Z, Szolcsányi J, Davis JB (2004) Daily body temperature rhythm and heat tolerance in TRPV1 knockout and capsaicin pretreated mice. Eur J Neurosci 19:142–144

    Google Scholar 

  • Szikszay M, Obál F, Obál F (1982) Dose-response relationships in the thermoregulatory effects of capsaicin. Naunyn-Schmiedeberg’s Arch Pharmacol 320:97–100

    CAS  Google Scholar 

  • Szőke É, Seress L, Szolcsányi J (2002a) 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 

  • Szőke É, Czéh G, Szolcsányi J, Seress L (2002b) Neonatal anandamide treatment results in prolonged mitochondrial damage in the vanilloid receptor type 1-immunoreactive B-type neurons of the rat trigeminal ganglion. Neuroscience 115:805–814

    PubMed  Google Scholar 

  • Szolcsányi J (1977) A pharmacological approach to elucidate the role of different nerve fibres and receptor endings in mediation of pain. J Physiol (Paris) 73:251–259

    Google Scholar 

  • Szolcsányi J (1980) Role of polymodal nociceptors in mediation of chemogenic pain and inflammatory hyperalgesia. In: Proceedings of the international congress of physiological science, vol 14, Budapest, p 734

    Google Scholar 

  • Szolcsányi J (1982) Capsaicin type pungent agents producing pyrexia. In: Milton AS (ed) Handbook of experimental pharmacology, pyretics and antipyretics, vol 60. Springer, Berlin, pp 437–478

    Google Scholar 

  • Szolcsányi J (1983a) Tetrodotoxin-resistant non-cholinergic neurogenic contraction evoked by capsaicinoids and piperine on the guinea-pig trachea. Neurosci Lett 42:83–88

    PubMed  Google Scholar 

  • Szolcsányi J (1983b) Disturbances of thermoregulation induced by capsaicin. J Therm Biol 8:207–212

    Google Scholar 

  • Szolcsányi J (1984) Capsaicin-sensitive chemoceptive neural system with dual sensory-efferent function. In: Chahl LA, Szolcsányi J, Lembeck F (eds) Antidromic vasodilatation and neurogenic inflammation. Akadémiai Kiadó, Budapest, pp 27–56

    Google Scholar 

  • Szolcsányi J (1987a) Selective responsiveness of polymodal nociceptors of the rabbit ear to capsaicin, bradykinin and ultra-violet irradiation. J Physiol 388:9–23

    PubMed Central  PubMed  Google Scholar 

  • Szolcsányi J (1987b) Capsaicin and nociception. Acta Physiol Hung 69:323–332

    PubMed  Google Scholar 

  • Szolcsányi J (1988) Antidromic vasodilatation and neurogenic inflammation. Agents Actions 23:4–11

    PubMed  Google Scholar 

  • Szolcsányi J (1990) Capsaicin, irritation and desensitization. Neurophysiological basis and future perspectives. In: Green BR, Mason JR, Kare MR (eds) Chemical senses: irritation, vol 2. Marcel Dekker, New York, pp 141–168

    Google Scholar 

  • Szolcsányi J (1993) Actions of capsaicin on sensory receptors. In: Wood JN (ed) Capsaicin in the study of pain. Academic Press, London, pp 1–26

    Google Scholar 

  • Szolcsányi J (1996) Capsaicin-sensitive sensory nerve terminals with local and systemic efferent functions: facts and scopes of an unorthodox neuroregulatory mechanism. Prog Brain Res 113:343–359

    PubMed  Google Scholar 

  • Szolcsányi J (2004) Forty years in capsaicin research for sensory pharmacology and physiology. Neuropeptides 38:377–384

    PubMed  Google Scholar 

  • Szolcsányi J (2005) Hot peppers, pain and analgesics. In: Malmberg AB, Bley KR (eds) Turning up to heat on pain: TRPV1 receptors in pain and inflammation. Birkhäuser Verlag, Basel, pp 3–22

    Google Scholar 

  • Szolcsányi J, Barthó L (1978) New type of nerve-mediated cholinergic contractions of the guinea-pig small intestine and its selective blockade by capsaicin. Naunyn-Schmiedeberg’s Arch Pharmacol 305:83–90

    Google Scholar 

  • Szolcsányi J, Barthó L (1979) Capsaicin-sensitive innervation of the guinea-pig taenia caeci. Naunyn-Schmiedebergs Arch Pharmacol 309:77–82

    PubMed  Google Scholar 

  • Szolcsányi J, Barthó L (1981) Impaired defense mechanism to peptic ulcer in the capsaicin-desensitized rat. In: Mózsik G, Hänninen O, Jávor T (eds) Gastrointestinal defense mechanisms. Advances in Physiological Sciences, vol 29. Akadémiai Kiadó, Pergamon Press, Oxford, pp 39–51

    Google Scholar 

  • Szolcsányi J, Barthó L (2001) Capsaicin-sensitive afferents and their role in gastroprotection: an update. J Physiol (Paris) 95:181–188

    Google Scholar 

  • Szolcsányi J, Jancsó-Gábor A (1973) Capsaicin and other pungent agents as pharmacological tools in studies on thermoregulation. In: Schönbaum E, Lomax P (eds) The pharmacology of thermoregulation. Karger, Basel, pp 395–409

    Google Scholar 

  • Szolcsányi J, Jancsó-Gábor A (1975a) Sensory effects of capsaicin congeners I. Relationship between chemical structure and pain-producing potency. Arzneim Forsch (Drug Res) 25:1877–1881

    Google Scholar 

  • Szolcsányi J, Jancsó-Gábor A (1975b) Analysis of the role warmth detectors by means of capsaicin under different conditions. In: Lomax P, Schönbaum E, Jacob J (eds). Karger, Basel, pp 331–338

    Google Scholar 

  • Szolcsányi J, Jancsó-Gábor A (1976) Sensory effects of capsaicin congeners II. Importance of chemical structure and pungency in desensitizing activity of capsaicin-type compounds. Arzneim Forsch (Drug Res) 26:33–37

    Google Scholar 

  • Szolcsányi J, Pintér E (2013) Transient receptor potential vanilloid 1 as a therapeutic target in analgesia. Expert Opin Ther Targets 17(6):641–657

    Google Scholar 

  • Szolcsányi J, Sándor Z (2012) Multisteric TRPV1 nocisensor: a target for analgesics. Trends Pharmacol Sci 33:646–655

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Szolcsányi J, Jancsó-Gábor A, Joó F (1975) Functional and fine structural characteristics of the sensory neuron blocking effect of capsaicin. Naunyn-Schmiedeberg’s Arch Pharmacol 287:157–169

    Google Scholar 

  • Szolcsányi J, Sann H, Pierau Fr-K (1986) Nociception in pigeon is not impaired by capsaicin. Pain 27:247–260

    PubMed  Google Scholar 

  • Szolcsányi J, Anton F, Reeh P, Handwerker HO (1988) Selective excitation by capsaicin of mechano-heat sensitive nociceptors in rat skin. Brain Res 446:262–268

    PubMed  Google Scholar 

  • Szolcsányi J, Szállási Á, Szállási Z, Joó F, Blumberg PM (1990) Resiniferatoxin: an ultrapotent selective modulator of capsaicin-sensitive primary afferent neurons. J Pharmacol Exp Ther 255:923–928

    PubMed  Google Scholar 

  • Szolcsányi J, Nagy J, Pethő G (1993) Effect of CP-96,345 a non-peptide substance P antagonist, capsaicin, resiniferatoxin and ruthenium red on nociception. Regul Pept 46:437–439

    PubMed  Google Scholar 

  • Szolcsányi J, Pórszász R, Pethő G (1994) Capsaicin and pharmacology of nociceptors. In: Besson JM, Guilbaud G, Ollat H (eds) Peripheral neurons in nociception: physio-pharmacological aspects. Elsevier, Amsterdam, pp 109–124

    Google Scholar 

  • Szolcsányi J, Pintér E, Helyes Zs (2011) Inhibition of the function of TRPV1-expressing nociceptive sensory neurons by somatostatin 4 receptor agonism: mechanism and therapeutical implications. Curr Top Med Chem 11:2253–2263

    PubMed  Google Scholar 

  • Thresh J, JC (1876) Capsaicin the active principle in Capsicum fruits. Pharm J Transact 7:21

    Google Scholar 

  • Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21:531–543

    CAS  PubMed  Google Scholar 

  • Tóth DM, Szőke É, Bölcskei K, Kvell K, Bender B, Bosze Z, Szolcsányi J, Sándor Z (2011) Nociception, neurogenic inflammation and thermoregulation in TRPV1 knockdown transgenic mice. Cell Mol Life Sci 68:2589–2601

    PubMed  Google Scholar 

  • Tóth-Kása I, Jancsó G, Bognár A, Husz S, Obál F (1986) Capsaicin prevents histamine-induced itching. Int J Clin Pharmacol Res 6:163–170

    PubMed  Google Scholar 

  • Touska F, Marsakova L, Teisinger J, Vlachova V (2011) A “cute” desensitization of TRPV1. Curr Pharm Biotechnol 12:122–129

    CAS  PubMed  Google Scholar 

  • Treede RD, Wagner T, Kern KU, Husstedt IVV, Arendt G, Birklein F, Cegla T, Freynhagen R, Gockel HH, Heskamp ML, Jager H, Joppich R, Maier C, Leffler A, Nagelein HH, Rolke R, Seddigh S, Sommer C, Stander S, Wasner G, Baron R (2013) Mechanism- and experience-based strategies to optimize treatment response to the capsaicin 8% cutaneous patch in patients with localized neuropathic pain. Curr Med Res Opin 29:527–538

    CAS  PubMed  Google Scholar 

  • Urbán L, Willetts J, Randic M, Papka RE (1985) The acute and chronic effects of capsaicin on slow excitatory transmission in rat dorsal horn. Brain Res 330:39–396

    Google Scholar 

  • Vay L, Gu C, McNaughton PA (2012) The thermo-TRP ion channel family: properties and therapeutic implications. Br J Pharmacol 165:787–801

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wall PD (1987) The central consequences of the application of capsaicin to one peripheral nerve in adult rat. Acta Physiol Hung 69:275–286

    CAS  PubMed  Google Scholar 

  • Wallengren J, Chen D, Sundler F (1999) Neuropeptide-containing C-fibers and wound healing in rat skin. Neither capsaicin nor peripheral neurotomy affect the rate of healing. Br J Dermatol 140:400–408

    CAS  PubMed  Google Scholar 

  • Weidner C, Schmelz M, Schmidt R, Hansson B, Handwerker HO, Torebjörk HE (1999) Functional attributes discriminating mechano-insensitive and mechano-responsive C nociceptors in human skin. J Neurosci 19:10184–10190

    CAS  PubMed  Google Scholar 

  • Welk E, Fleischer E, Petsche U, Handwerker HO (1984) Afferent C-fibers in rats after neonatal capsaicin treatment. Pflügers Arch 400:66–71

    CAS  PubMed  Google Scholar 

  • Winter J, Dray A, Wood JN, Yeats JC, Bevan S (1990) Cellular mechanism of action of resiniferatoxin: a potent sensory neuron excitotoxin. Brain Res 520:131–140

    CAS  PubMed  Google Scholar 

  • Wood JN, Winter J, James IF, Rang HP, Yeats J, Bevan S (1988) Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture. J Neurosci 8:3208–3220

    CAS  PubMed  Google Scholar 

  • Woolf CJ (2011) Central sensitization: Implications for the diagnosis and treatment of pain. Pain 152:S2–S15

    PubMed Central  PubMed  Google Scholar 

  • Xia R, Samad TA, Btesh J, Jiang LH, Kays I, Stjernborg L, Dekker N (2011) TRPV1 signaling: mechanistic understanding and therapeutic potential. Curr Top Med Chem 11:2180–2189

    CAS  PubMed  Google Scholar 

  • Yaks TL, Farb DH, Leeman SE, Jessell TM (1979) Intrathecal capsaicin depletes substance P in the rat spinal cord and produces prolonged thermal analgesia. Science 206:481–483

    Google Scholar 

Download references

Acknowledgments

This work was supported by the grants of OTKA NK-78059 and SROP 4.2.2.A-11/1/KONV-2012-0024.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Szigeti u. 12, Pécs, H-7624, Hungary

    János Szolcsányi

Authors
  1. János Szolcsányi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to János Szolcsányi .

Editor information

Editors and Affiliations

  1. Department of Toxicology and Narcotics, National Research Center, Cairo, Egypt

    Omar M. E. Abdel-Salam

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Basel

About this chapter

Cite this chapter

Szolcsányi, J. (2014). Capsaicin and Sensory Neurones: A Historical Perspective. In: Abdel-Salam, O. (eds) Capsaicin as a Therapeutic Molecule. Progress in Drug Research, vol 68. Springer, Basel. https://doi.org/10.1007/978-3-0348-0828-6_1

Download citation

Publish with us

Policies and ethics

Search

Navigation