Skip to main content

Advertisement

SpringerLink
Log in

Thermosensitive Transient Receptor Potential (TRP) Channel Agonists and Their Role in Mechanical, Thermal and Nociceptive Sensations as Assessed Using Animal Models

  • Published:
Chemosensory Perception

Abstract

Introduction

The present paper summarizes research using animal models to investigate the roles of thermosensitive transient receptor potential (TRP) channels in somatosensory functions including touch, temperature, and pain. We present new data assessing the effects of eugenol and carvacrol, agonists of the warmth-sensitive TRPV3, on thermal, mechanical, and pain sensitivity in rats.

Methods

Thermal sensitivity was assessed using a thermal preference test, which measured the amount of time the animal occupied one of two adjacent thermoelectric plates set at different temperatures. Pain sensitivity was assessed as an increase in latency of hindpaw withdrawal away from a noxious thermal stimulus directed to the plantar hindpaw (Hargreaves’ test). Mechanical sensitivity was assessed by measuring the force exerted by an electronic von Frey filament pressed against the plantar surface that elicited withdrawal.

Results

Topical application of eugenol and carvacrol did not significantly affect thermal preference, although there was a trend toward avoidance of the hotter surface in a 30 vs. 45 °C preference test for rats treated with 1 or 10 % eugenol and carvacrol. Both eugenol and carvacrol induced a concentration-dependent increase in thermal withdrawal latency (analgesia), with no significant effect on mechanosensitivity.

Conclusions

The analgesic effect of eugenol and carvacrol is consistent with previous studies. The tendency for these chemicals to increase the avoidance of warmer temperatures suggests a possible role for TRPV3 in warmth detection, also consistent with previous studies. Additional roles of other thermosensitive TRP channels (TRPM8 TRPV1, TRPV2, TRPV4, TRPM3, TRPM8, TRPA1, and TRPC5) in touch, temperature, and pain are reviewed.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Albin KC, Carstens MI, Carstens E (2008) Modulation of oral heat and cold pain by irritant chemicals. Chem Senses 33:3–15

    Article  CAS  Google Scholar 

  • Alessandri-Haber N, Dian OA, Joseph EK, Reichling D, Levin JD (2006) A transient receptor potential vanilloid 4-dependent mechanism of hyperalgesia is engaged by concerted action of inflammatory mediators. J Neurosci 26(14):3864–3874

    Article  CAS  Google Scholar 

  • Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, Patapoutian A (2004) Noxious cold ion channel TRPA1 is activate dby pungent compounds and bradykinin. Neuron 41:849–857

    Article  CAS  Google Scholar 

  • Bang S, Kim KY, Yoo S, Lee SH, Hwang SW (2007) Transient receptor potential V2 expressed in sensory neurons is activated by probenecid. Neurosci Lett 425:120–122

    Article  CAS  Google Scholar 

  • Bang S, Yoo S, Yang TJ, Cho H, Hwang SW (2010) Farnesyl pyrophosphate is a novel pain-producing molecule via specific activation of TRPV3. J Biol Chem 285(25):19362–19371

    Article  CAS  Google Scholar 

  • Baumann TK, Simone DA, Shain CN, LaMotte RH (1991) Neurogenic hyperalgesia: the search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia. J Neurophysiol 66(1):212–227

    CAS  Google Scholar 

  • Bautista DM, Movahed P, Hinman A, Axelsson HE, Sterner O, Hogestatt ED, Julius D (2005) Pungent products form garlic activate the sensory ion channel TRPA1. PNAS 102:12248–12252

    Article  CAS  Google Scholar 

  • Bautista DM, Jordt S-E, Nikai T, Tsuruda PR, Read AJ, Poblete J, Yamoah EN, Basbaum AI, Julius D (2006) TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124:1269–1282

    Article  CAS  Google Scholar 

  • Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt S-E, Julius D (2007) The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448:204–209

    Article  CAS  Google Scholar 

  • Behrendt HJ, Germann T, Gillen C, Hatt H, Jostock R (2004) Characterization of the mouse cold menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay. Br J Pharmacol 141:737–745

    Article  CAS  Google Scholar 

  • Bhanghoo S, Ren D, Miller RJ, Henry KJ, Lineswala J, Hamdouchi C, Li B, Monahan PE, Chan DM, Ripsch MS, White FA (2007) Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nocieptors. Mol Pain 3:38

    Article  CAS  Google Scholar 

  • Brenderson JD, Kym PR, Szallasi A (2013) Targeting TRP channels for pain relief. Eur J Pharmacol 716(1–3):61–76

    Article  CAS  Google Scholar 

  • Brierly SM, Castro J, Harrington AM, Hughes PA, Page AJ, Rychkov GY, Blackshaw LA (2011) TRPA1 contributes to specific mechanically activated currents and sensory neuron mechanical hypersensitivity. J Physiol 589:3575–3593

    Article  CAS  Google Scholar 

  • Caterina MJ, Julius D (2001) The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci 24:487–517

    Article  CAS  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

    Article  CAS  Google Scholar 

  • Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D (1999) A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398:436–441

    Article  CAS  Google Scholar 

  • Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313

    Article  CAS  Google Scholar 

  • Chen J, Luo C, Li HL, Chen HS (1999) Primary hyperalgesia to mechanical and heat stimuli following subcutaneous bee venom injection into the plantar surface of hindpaw in the conscious rat: a comparative study with the formalin test. Pain 83:67–76

    Article  CAS  Google Scholar 

  • Chuang H-H, Prescott ED, Kong H, Shields S, Jordt S-E, Basbaum AI, Chao MV, Julius D (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411:957–962

    Article  CAS  Google Scholar 

  • Chung MK, Lee H, Mizuno A, Caterina MJ (2004) TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. J Biol Chem 279:21569–21575

    Article  CAS  Google Scholar 

  • Cliff MA, Green BG (1994) Sensory irritation and coolness produced by menthol: evidence for selective desensitization of irritation. Physiol Behav 56:1021–1029

    Article  CAS  Google Scholar 

  • Colburn RW, Lubin M, Stone DJ Jr, Wang Y, Lawrence D, D’Andrea MR, Brandt MR, Liu Y, Flores CM, Qin N (2007) Attenuated cold sensitivity in TRPM8 null mice. Neuron 54:379–386

    Article  CAS  Google Scholar 

  • Corey DP, Garcia-Anoveros J, Holt JR, Kwan KY, Lin SY, Vollrath MA, Amalfitano A, Cheung ELM, Derfler BH, Duggan A, Geleoc GSG, Gray PA, Hoffman MP, Rehm HL, Tamasauskas D, Zhang DS (2004) TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature 432:723–730

    Article  CAS  Google Scholar 

  • Cortright DN, Krause JE, Broom DC (2007) TRP channels and pain. Biochim Biophys Acta 1772:978–988

    Article  CAS  Google Scholar 

  • Craft RM, Kandasamy R, Davis SM (2013) Sex differences in anti-allodynic, anti-hyperalgesic and anti-edema effects of Ä9-tetrahydrocannabinol in the rat. Pain 154(9):1709–1717

    Article  CAS  Google Scholar 

  • da Costa DSM, Meotii FC, Andrade EL, Leal PC, Motta EM, Calixto JB (2010) The involvement of the transient receptor potential A1 (TRPA1) in the maintenance of mechanical and cold hyperalgesia in persistent inflammation. Pain 148(3):431–437

    Article  CAS  Google Scholar 

  • del Camino D, Murphy S, Heiry M, Barrett LB, Earley TJ, Cook CA, Petrus MJ, Zhao M, D’Amours M, Deering N, Brenner GJ, Costigan M, Hayward NJ, Chong JA, Fanger CM, Woolf CJ, Patapoutian A, Moran MM (2010) TRPA1 contributes to cold hypersensitivity. J Neurosci 30(45):15165–15174

    Article  CAS  Google Scholar 

  • Dessirier JM, Nguyen N, Sieffermann JM, Carstens E, O’Mahony M (1999) Oral irritant properties of piperine and nicotine: psychophysical evidence for asymmetrical desensitization effects. Chem Senses 24(4):405–413

    Article  CAS  Google Scholar 

  • Dessirier JM, O’Mahony M, Carstens E (2001) Oral irritant properties of menthol: sensitizing and desensitizing effects of repeated application and cross-desensitization to nicotine. Physiol Behav 73:25–36

    Article  CAS  Google Scholar 

  • Dhaka A, Murray AN, Mathur J, Earley TJ, Petrus MJ, Patapoutian A (2007) TRPM8 is required for cold sensation in mice. Neuron 54:371–378

    Article  CAS  Google Scholar 

  • Eid S, Crown E, Moore E, Liang H, Choong K-C, Dima S, Henze D, Kane S, Urban M (2008) HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity. Mol Pain 4:48–57

    Article  CAS  Google Scholar 

  • Flemming PK, Dedman AM, Xu S-Z, Li J, Zeng F, Naylor J, Benham CD, Bateson AN, Muraki K, Beech DJ (2006) Sensing of lysophospholipids by TRPC5 calcium channel. Biol Chem 281:4977–4982

    Article  CAS  Google Scholar 

  • Gilchrist HD, Allard BL, Simone DA (1996) Enhanced withdrawal responses to heat and mechanical stimuli following intraplantar injection of capsaicin in rats. Pain 67:179–188

    Article  CAS  Google Scholar 

  • Grant AD, Cottrell GS, Amadesi S, Trevisani M, Nicoletti P, Materazzi S, Altier C, Cenac N, Zamponi GW, Bautista-Cruz F, Lopez CB, Joseph EK, Levine JD, Liedtke W, Vanner S, Vergnolle N, Geppetti P, Bunnett NW (2007) Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice. J Physiol 578(3):715–733

    Article  CAS  Google Scholar 

  • Green BG (1986) Menthol inhbits the perception of warmth. Physiol Behav 38:833–838

    Article  CAS  Google Scholar 

  • Green BG (1990) Sensory characteristics of camphor. J Invest Dermatol 94(5):662–666

    Article  CAS  Google Scholar 

  • Green BG (1992) The sensory effects of l-menthol on human skin. Somatosens Mot Res 9:235–244

    Article  CAS  Google Scholar 

  • Green BG (1993) Evidence that removal of capsaicin accelerates desensitization on the tongue. Neurosci Lett 150:44–48

    Article  CAS  Google Scholar 

  • Green BG (2005) Lingual heat and cold sensitivity following exposure to capsaicin or menthol. Chem Senses 30:201–202

    Article  Google Scholar 

  • Green BG, McAuliffe BL (2000) Menthol desensitization of capsaicin irritation: evidence of a short-term anti-nociceptive effect. Physiol Behav 68:631–639

    Article  CAS  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

    Article  CAS  Google Scholar 

  • Guler AD, Lee HS, Iida T, Shimizu I, Tominaga M, Caterina M (2002) Heat-evoked activation of the ion channel, TRPV4. J Neurosci 22:6408–6414

    CAS  Google Scholar 

  • Hatem S, Attal N, Willer J-C, Bouhassira D (2006) Psychophysical study of the effects of topical application of menthol in healthy volunteers. Pain 122:190–196

    Article  CAS  Google Scholar 

  • Hisanaga E, Nagasawa M, Ueki K, Kulkarni RN, Mori M, Kojima I (2009) Regulation of calcium-permeable TRPV2 channel by insulin in pancreatic beta-cells. Diabetes 58:174–184

    Article  CAS  Google Scholar 

  • Hoffmann A, Grimm C, Kraft R, Goldbaum O, Wrede A, Nolte C, Hanisch U-K, Landsberg CR, Brück W, Kettenmann H, Harteneck C (2010) TRPM3 is expressed in sphingosine-responsive myelinating oligodendrocytes. J Neurochem 114:654–665

    Article  CAS  Google Scholar 

  • Hong Y, Abbott FV (1994) Behavioral effects of intraplntar injection of inflammatory mediators in the rat. Neuroscience 63(3):827–836

    Article  CAS  Google Scholar 

  • Horvath G, Kekesi G, Nagy E, Benedek G (2008) The role of TRPV1 receptors in the antinociceptive effect of anandamide at spinal level. Pain 134:277–284

    Article  CAS  Google Scholar 

  • Hu HZ, Xiao R, Wang C, Gao N, Colton CK, Wood JD, Zhu MX (2006) Potentiation of TRPV3 channel function by unsaturated fatty acids. J Cell Physiol 208:201–212

    Article  CAS  Google Scholar 

  • Huang SM, Li X, Yu Y, Wang J, Caterina MJ (2011) TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation. Mol Pain 7:37

    Article  CAS  Google Scholar 

  • Ichikawa H, Sugimoto T (2000) Vanillioid receptor 1-like receptor-immunoreactive primary sensory neurons in the rat trigeminal nervous system. Neuroscience 101:719–725

    Article  CAS  Google Scholar 

  • Inada H, Iida T, Tominaga M (2006) Different expression patterns of TRP genes in murine B and T lymphocytes. Biochem Biophys Res Commun 350(3):762–767

    Article  CAS  Google Scholar 

  • Inoue M, Xie W, Matsushita Y, Chun J, Aoki J, Ueda H (2008) Lysophosphatidylcholine induces neuropathic pain through an action of autotaxin to generate lysophosphatidic acid. Neuroscience 152(2):296–298

    Article  CAS  Google Scholar 

  • Jordt S-E, Bautista DM, Chuang H-H, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–265

    Article  CAS  Google Scholar 

  • Julius D (2013) TRP channels and pain. Annu Rev Cell Dev Biol 29:355–384

    Article  CAS  Google Scholar 

  • Karai L, Brown DC, Mannes AJ, Connelly ST, Brown J, Gandal M, Wellisch OM, Neubert JK, Olah Z, Iadarola MJ (2004) Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control. J Clin Invest 113(9):1344–1352

    Article  CAS  Google Scholar 

  • Karashima Y, Damann N, Prenen J, Talavera K, Segal A, Voets T, Nilius B (2007) Bimodal action of menthol on the transient receptor potential channel TRPA1. J Neurosci 27:9874–9884

    Article  CAS  Google Scholar 

  • Karashima Y, Talavera K, Everaerts W, Janssens A, Kwan KY, Vennekens R, Nilius B, Voets T (2009) TRPA1 acts as a cold sensor in vitro and in vivo. Proc Natl Acad Sci 106:1273–1278

    Article  CAS  Google Scholar 

  • Karim F, Hu H-J, Adwanikar H, Kaplan D, Gereau RW (2006) Impaired inflammatory pain and thermal hyperalgesia in mice expressing neuron-specfic dominant negative mitogen activated protein kinase kinase (MEK). Mol Pain 2:2

    Article  CAS  Google Scholar 

  • Kashiba H, Uchida Y, Takeda D, Nishigori A, Ueda Y, Kuribayashi K, Ohshima M (2004) TRPV2-immunoreactive intrinsic neurons in the rat intestine. Neurosci Lett 366:193–196

    Article  CAS  Google Scholar 

  • Kerstein P, del Camino D, Moran M, Stucky C (2009) Pharmacological blockade of TRPA1 inhibits mechanical firing in nociceptors. Mol Pain 5:19–31

    Article  CAS  Google Scholar 

  • Klein AH, Sawyer CM, Iodi Carstens M, Tsagareli MG, Tsiklauri N, Carstens E (2010) Topical application of l-menthol induces heat analgesia, mechanical allodynia, and a biphasic effect on cold sensitivity in rats. Behav Brain Res 212(2):179–186

    Article  CAS  Google Scholar 

  • Klein AH, Sawyer CM, Zanotoo KL, Ivanov MA, Cheung S, Carstens MI, Furrer S, Simons CT, Slack JP, Carstens E (2011) A tingling sanshool derivative excites primary sensory neurons and elicits nocifensive behavior in rats. J Neurophysiol 105(4):1701–1710

    Article  CAS  Google Scholar 

  • Klein AH, Sawyer CM, Takechi K, Davoodi A, Ivanov MA, Carstens MI, Carstens E (2012) Topical hindpaw application of l-menthol decreases resonsiveness to heat with biphasic effects on cold sensitivity of rat lumbar dorsal horn neurons. Neuroscience 219:234–242

    Article  CAS  Google Scholar 

  • Klein AH, Carstens MI, Carstens E (2013) Eugenol and carvacrol induce temporally desensitizing patterns of oral irritation and enhance innocuous warmth and noxious heat sensation on the tongue. Pain 154(10):2078–2087

    Article  CAS  Google Scholar 

  • Klein AH, Joe CL, Davoodi A, Takechi K, Carstens MI, Carstens E (2014) Eugenol and carvacrol excite first- and second-order trigeminal neurons and enhance their heat-evoked responses. Neuroscience 271:45–55

    Article  CAS  Google Scholar 

  • Knowlton WM, Bifolck-Fisher A, Bautista DM, McKemy DD (2010) TRPM8, but not TRPA1, is required for neural and behavioral responses to acute noxious cold temperatures and cold-mimetics in vivo. Pain 150:340–350

    Article  CAS  Google Scholar 

  • Knowlton WM, Palkar R, Lippoldt EK, McCoy DD, Baluch F, Chen J, McKemy DD (2013) A sensory labeled-line for cold: TRPM8-expressing sensory neurons define the cellular basis for cold, cold pain, and cooling-mediated analgesia. J Neurosci 33(7):2837–2848

    Article  CAS  Google Scholar 

  • Kobayashi K, Fukuoka T, Obata K, Yamanaka H, Dai Y, Tokunaga A, Noguchi K (2005) Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with a-delta/c-fibers and colocalization with trk receptors. J Comp Neurol 493:596–606

    Article  CAS  Google Scholar 

  • Koltzenburg M, Lundberg LE, Torebjörk HE (1992) Dynamic and static components of mechanical hyperalgesia in human hairy skin. Pain 51:207–221

    Article  CAS  Google Scholar 

  • Kwan KY, Allchorne AJ, Vollrath MA, Christensen AP, Zhang DS, Woolf CJ, Corey DP (2006) TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron 50:277–289

    Article  CAS  Google Scholar 

  • Kwan KY, Glazer JM, Corey DP, Rice FL, Stucky CL (2009) TRPA1 modulates mechanotransduction in cutaneous sensory neurons. J Neurosci 29:4808–4819

    Article  CAS  Google Scholar 

  • LaMotte RH, Shain CN, Simone DA, Tsai EF (1991) Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms. J Neurophysiol 66(1):190–211

    CAS  Google Scholar 

  • Latorre R, Vargas G, Orta G, Brauchi S (2007) Voltage and temperature gating of ThermoTRP channels. In: Liedtke WB, Heller S (eds) TRP ion channel function in sensory transduction and cellular signaling cascades, chapter 21. CRC, Boca Raton

    Google Scholar 

  • Lawson JJ, McIlwrath SL, Woodbury CJ, Davis BM, Koerber HR (2008) TRPV1 unlike TRPV2 is restricted to a subset of mechanically insensitive cutaneous nociceptors responding to heat. J Pain 9:298–308

    Article  CAS  Google Scholar 

  • Lee H, Iida T, Mizuno A, Suzuki M, Caterina MJ (2005) Altered thermal selection behavior in mice lacking transient receptor potential vanilloid 4. J Neurosci 25(5):1304–1310

    Article  CAS  Google Scholar 

  • Leffler A, Linte RM, Nau C, Reeh P, Babes A (2007) A high-threshold heat-activated channel in cultured rat dorsal root ganglion neurons resembles TRPV2 and is blocked by gadolinium. Eur J Neurosci 26:12–22

    Article  Google Scholar 

  • Levine JD, Alessandri-Haber N (2007) TRP channels: targets for the relief of pain. Biochim Biophys Acta 1772:989–1003

    Article  CAS  Google Scholar 

  • Lewinter RD, Skinner K, Julius D, Basbaum AI (2004) Immunoreactive TRPV-2 (VRL-1), a capsaicin receptor homolog, in the spinal cord of the rat. J Comp Neurol 470:400–408

    Article  CAS  Google Scholar 

  • Liedtke W, Friedman JM (2003) Abnormal osmotic regulation of TRPV4 −/− mice. Proc Natl Acad Sci 100:13698–13708

    Article  CAS  Google Scholar 

  • Liedtke W, Kim C (2005) Functionality of the TRPV subfamily of TRP ion channels: add mechano-TRP and osmo-TRP to the lexicon! Cell Mol Life Sci 62:2985–3001

    Article  CAS  Google Scholar 

  • Macpherson LJ, Hwang SW, Miyamoto T, Dubin AE, Patapoutian A, Story GM (2006) More than cool: promiscuous relationships of menthol and other sensory compounds. Mol Cell Neurosci 32:335–343

    Article  CAS  Google Scholar 

  • Macpherson LJ, Xiao B, Kwan KY, Petrus MJ, Dubin AE, Hwang SW, Cravatt B, Corey DP, Patapoutian A (2007) An ion channel essential for sensing chemical damage. J Neurosci 27(42):11412–11415

    Article  CAS  Google Scholar 

  • Madrid R, Donovan-Rodriguez T, Meseguer V, Acosta MC, Belmonte C, Viana F (2006) Contribution of TRPM8 channels to cold transduction in primary sensory neurons and peripheral nerve terminals. J Neurosci 26:12512–12525

    Article  CAS  Google Scholar 

  • Malkia A, Madrid R, Meseguer V, de la Pena E, Valero M, Belmonte C, Viana F (2007) Bidirectional shifts of TRPM8 channel gating by temperature and chemical agents modulate the cold sensitivity of mammalian thermoreceptors. J Physiol Lond 581:155–174

    Article  CAS  Google Scholar 

  • Marics I, Malapert P, Reynders A, Gaillard S, Moqrich A (2014) Acute heat-evoked temperature sensation is impaired but not abolished in mice lacking TRPV1 and TRPV3 channels. PLoS One 9(6):e99828

    Article  CAS  Google Scholar 

  • McKemy DD, Neuhausser WM, Julius D (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416:52–58

    Article  CAS  Google Scholar 

  • McNamara FN, Randall A, Gunthorpe MJ (2005) Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1). Br J Pharmacol 144:781–790

    Article  CAS  Google Scholar 

  • McNamara CR, Mandel-Brehm J, Bautista DM, Siemenst J, Deranian KL, Zhao M, Hayward NJ, Chong JA, Julius D, Moran MM, Fanger CM (2007) TRPA1 mediates formain-induced pain. Proc Natl Acad Sci 104:13525–13530

    Article  CAS  Google Scholar 

  • Merrill AW, Cuellar JM, Judd JH, Carstens MI, Carstens E (2008) of TRPA1 agonists mustard oil and cinnamaldehyde on lumbar spinal wide-dynamic range neuronal responses to innocuous and noxious cutaneous stimuli in rats. J Neurophysiol 99:415–425

    Article  CAS  Google Scholar 

  • Meseguer V, Alpizar YA, Luis E, Tajada S, Denlinger B, Fajardo O, Manenschijn J-A, Fernández-Peña C, Talavera A, Kichko T, Navia B, Sánchez A, Señarís R, Reeh P, Pérez-García MT, López-López JR, Voets T, Belmonte C, Talavera K, Viana F (2014) TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins. Nat Commun 5:3125

    Article  CAS  Google Scholar 

  • Mizuno A, Imai M, Suzuki M (2003) Impaired osmo-sensation in mice lacking TRPV4. J Pharm Sci 91:229P

    Article  Google Scholar 

  • Mogil JS (2009) Animal models of pain: progress and challenges. Nat Rev Neurosci 10:283–294

    Article  CAS  Google Scholar 

  • Mogil JS, Davis KD, Derbyshire SW (2012) The necessity of animal models in pain research. Pain 151:12–17

    Article  Google Scholar 

  • Moilanen LJ, Laavola M, Kukkonen M, Korhonen R, Leppänen T, Högestätt ED, Zygmunt PM, Nieminen RM, Moilanen E (2012) TRPA1 contributes to the acute inflammatory response and mediates carrageenan-induced paw edema in the mouse. Sci Rep 2:380

    Article  CAS  Google Scholar 

  • Moqrich A, Hwang SW, Earley TJ, Petrus MJ, Murrary AN, Spencer KSR, Andahazy M, Story GM, Patapoutian A (2005) Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 307:1468–1472

    Article  CAS  Google Scholar 

  • Morenilla-Palao C, Luis E, Fernándex-Peña C, Quintero E, Weaver JL, Bayliss DA, Viana F (2014) Ion channel profile of TRPM8 cold receptors reveals a role of TASK-3 potassium channels in thermosensation. Cell Rep 8(5):1571–1582

    Article  CAS  Google Scholar 

  • Moriyama T, Higashi T, Togashi K, Iida T, Segi E, Sugimoto Y, Tominaga T, Narumiya S, Tominaga M (2005) Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain 1:3

    Article  CAS  Google Scholar 

  • Muraki K, Iwata Y, Katanosaka Y, Ito T, Ohya S, Shigekawa M, Imaizumi Y (2003) TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes. Circ Res 93:829–838

    Article  CAS  Google Scholar 

  • Myers BR, Julius D (2007) TRP channel structural biology: new roles for an old fold. Neuron 54:847–850

    Article  CAS  Google Scholar 

  • Namer B, Seifert F, Handwerker HO, Maihöfner C (2005) TRPA1 and TRPM8 activation in humans: effects of cinnamaldehyde and menthol. NeuroReport 16:955–959

    Article  CAS  Google Scholar 

  • Nealen ML, Gold MS, Thut PD, Caterina MJ (2003) TRPM8 mRNA is expressed in a subset of cold-responsive trigeminal neurons from rat. J Neurophysiol 90:515–520

    Article  CAS  Google Scholar 

  • Neddermeyer TJ, Flühr K, Lötsch J (2008) Principle components analysis of pain thresholds to thermal, electrical, and mechanical stimuli suggests a predominant common source of variance. Pain 138:286–291

    Article  Google Scholar 

  • Neubert JK, Widmer CG, Malphurs W, Rossi HL, Vierck JCJ, Caudle RM (2005) Use of a novel thermal operant behavioral assay for characterization of orofacial pain sensitivity. Pain 116:386–395

    Article  Google Scholar 

  • Nilius B, Owsianik G, Voets T, Peters JA (2007) Transient receptor potential cation channels in disease. Physiol Rev 87:165–217

    Article  CAS  Google Scholar 

  • Nishijima CM, Ganev EG, Mazzardo-Martins L, Martins DF, Rocha LRM, Santos ARS, Hiruma-Lima CA (2014) Citral: a monoterpene with prophylactic and therapeutic anti-nociceptive effects in experimental models of acute and chronic pain. Eur J Pharmacol 736(5):16–25

    Article  CAS  Google Scholar 

  • Nozadze I, Tsiklauri N, Gurtskaia G, Tsagareli MG (2014) Behavioral study of TRPA1 and TRPV1 channels relationship in rats. Bull Georgian Natl Acad Sci 8(1):2014

    Google Scholar 

  • Okada T, Shimizu S, Wakamori M, Maeda A, Kurosaki T, Takada N, Imoto K, Mori Y (1998) Molecular cloning and functional characterization of a novel receptor-activated TRP Ca2+ channel from mouse brain. J Biol Chem 273:10279–10287

    Article  CAS  Google Scholar 

  • Park CK, Li HY, Yeon KY, Jung SJ, Choi SY, Lee SJ, Lee S, Park K, Kim JS, Oh SB (2006) Eugenol inhibits sodium currents in dental afferent neurons. J Dent Res 85(10):900–904

    Article  CAS  Google Scholar 

  • Park CK, Kim K, Jung SJ, Kim MJ, Ahn DK, Hong SD, Kim JS, Oh SB (2009) Molecular mechanism for local anesthetic action of eugenol in the rat trigeminal system. Pain 144(1–2):84–94

    Article  CAS  Google Scholar 

  • Park U, Vastani N, Guan Y, Raja SN, Koltzenburg M, Caterina MJ (2011) TRPV2 knockout mice are susceptible to perinatal lethality but display normal thermal and mechanical nociception. J Neurosci 31(32):11425–11436

    Article  CAS  Google Scholar 

  • Patapoutian A, Peier AM, Story GM, Viswanath V (2003) ThermoTRP channels and beyond: mechanisms for temperature sensation. Nat Rev Neurosci 4:529–539

    Article  CAS  Google Scholar 

  • Patapoutian A, Tate S, Woolf CJ (2009) Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Discov 8:55–68

    Article  CAS  Google Scholar 

  • Patel T, Ishiuji Y, Yosipovitch G (2007) Menthol: a refreshing look at this ancient compound. J Am Acad Dermatol 57:873–878

    Article  Google Scholar 

  • Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A (2002) A TRP channel that senses cold stimuli and menthol. Cell 108:705–715

    Article  CAS  Google Scholar 

  • Petitjean H, Hugel S, Barthas F, Bohren Y, Barrot M, Yalcin I, Schlichter R (2014) Activation of transient receptor potential vanilloid 2-expressing primary afferents stimulates synaptic transmission in the deep dorsal horn of the rat spinal cord and elicits mechanical hyperalgesia. Eur J Neurosci 40(8):3189–3201 (in press)

    Article  Google Scholar 

  • Petrus M, Peier AM, Bandell M, Hwang SW, Huynh T, Olney N, Jegla T, Patapoutian A (2007) A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. Mol Pain 3:40–47

    Article  CAS  Google Scholar 

  • Philipp S, Hambrecht J, Braslavski L, Schroth G, Freichel M, Murakami M, Cavalie A, Flockerzi V (1998) A novel capacitative calcium entry channel expressed in excitable cells. EMBO J 17:4274–4282

    Article  CAS  Google Scholar 

  • Pogorzala LA, Mishra SK, Hoon MA (2013) The cellular code for mammalian thermosensation. J Neurosci 33(13):5533–5541

    Article  CAS  Google Scholar 

  • Potenzieri C, Brink TS, Simone DA (2009) Excitation of cutaneous C nociceptors by intraplatar administration of anadamide. Brain Res 1268:38–47

    Article  CAS  Google Scholar 

  • Prescott J, Swain-Campbell N (2000) Responses to repeated oral irritation by capsaicin, cinnam-aldehyde and ethanol in PROP tasters and non-tasters. Chem Senses 25:239–246

    Article  CAS  Google Scholar 

  • Price DD, Dubner R (1977) Mechanisms of first and second pain in the peripheral and central nervous systems. J Invest Dermatol 69:167–171

    Article  CAS  Google Scholar 

  • Qin N, Neeper MP, Liu Y, Hutchinson TL, Lubin ML, Flores CM (2008) TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. J Neurosci 28:6231–6238

    Article  CAS  Google Scholar 

  • Rau KK, Jiang N, Johnson RD, Cooper BY (2007) Heat sensitization in skin and muscle nociceptors expressing distinct combinations of TRPV1 and TRPV2 protein. J Neurophysiol 97:2651–2662

    Article  CAS  Google Scholar 

  • Reid G, Babes A, Pluteanu F (2002) A cold- and menthol-activated current in rat dorsal root ganglion neurones: properties and role in cold transduction. J Physiol Lond 545:595–614

    Article  CAS  Google Scholar 

  • Robbins A, Kurose M, Winterson BJ, Meng ID (2012) Menthol activatin onf cornea cool cells induces TRPM8-mediated lacrimation but not nociceptive responses in rodents. Invest Opthalmol Vis Sci 53(11):7034–7042

    Article  CAS  Google Scholar 

  • Roboisson P, Dallel R (2004) The orofacial formalin test. Neurosci Biobehav Rev 28(2):219–226

    Article  Google Scholar 

  • Rohacs T, Lopes CMB, Michailidis I, Logothetis DE (2005) PI(4,5)P-2 regulates the activation and desensitization of TRPM8 channels through the TRP domain. Nat Neurosci 8:626–634

    Article  CAS  Google Scholar 

  • Rossi HL, Vierck CJ, Caudle RM, Neubert JK (2006) Characterization of cold sensitivity and thermal preference using an operant orofacial assay. Mol Pain 2:37–46

    Article  Google Scholar 

  • Ryborg AK, Deleuran B, Søgaard H, Kragbaile K (2000) Intracutaneous injection of lysophosphatidylcholine induces skin inflammation and accumulation of leukocytes. Acta Derm Vereneol 80(4):242–246

    Article  CAS  Google Scholar 

  • Sakurada T, Katsumata K, Tan-No K, Sakurada S, Kisara K (1992) The capsaicin test in mice for evaluating tachykinin antagonists in the spinal cord. Neuropharmacology 31:1279–1285

    Article  CAS  Google Scholar 

  • Sawyer CM, Carstens MI, Carstens E (2009) Mustard oil enhances spinal neuronal responses to noxious heat but not cooling. Neurosci Lett 461:271–274

    Article  CAS  Google Scholar 

  • Simone DA, Ochoa J (1991) Early and late effects of prolonged topical capsaicin on cutaneous sensibility and neurogenic vasodilatation in humans. Pain 47:285–294

    Article  CAS  Google Scholar 

  • Simone DA, Ngeow JYF, Putterman GJ, LaMotte RH (1987) Hyperalgesia to heat after intradermal injection of capsaicin. Brain Res 418:201–203

    Article  CAS  Google Scholar 

  • Simone DA, Sorkin LS, Oh U, Chung JM, Owens C, LaMotte RH, Willis WD (1991) Neurogenic hyperalgesia: central neural correlates in responses of spinothalamic tract neurons. J Neurophysiol 66(1):228–246

    CAS  Google Scholar 

  • Simons CT, Carstens MI, Carstens E (2003) Oral irritation by mustard oil: self-desensitization and cross-desensitization with capsaicin. Chem Senses 28:459–465

    Article  CAS  Google Scholar 

  • Smith GD, Gunthorpe MJ, Kelsell RE, Hayes PD, Reilly P, Facer P, Wright JE, Jerman JC, Walhin JP, Ooi L, Egerton J, Charles KJ, Smart D, Randall AD, Anand P, Davis JB (2002) TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature 418:186–190

    Article  CAS  Google Scholar 

  • Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW, McIntyre P, Jegla T, Bevan S, Patapoutian A (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112:819–829

    Article  CAS  Google Scholar 

  • Stotz SC, Vriens J, Martyn D, Clardy D, Clapham DE (2008) Citral sensing by transient receptor potential channels in dorsal root ganglion neurons. PLoS One 3(5):e2082

    Article  CAS  Google Scholar 

  • Stucky CL, Dubin AE, Jeske NA, Malin SA, McKemy DD, Story GM (2009) Roles of transient receptor potential channels in pain. Brain Res Rev 60:2–23

    Article  CAS  Google Scholar 

  • Sugiura T, Tominaga M, Katsuya H, Mizumura K (2002) Bradykinin lowers the threshold temperature for heat activation of vanilloid receptor 1. J Neurophysiol 88:544–548

  • Suzuki M, Mizuno A, Kodaira K, Imai M (2003) Impaired pressure sensation in mice lacking TRPV4. J Biol Chem 171:22664–22668

    Article  CAS  Google Scholar 

  • Swandulla D, Carbone E, Schäfer K, Lux HD (1987) Effect of menthol on two types of Ca currents in cultured sensory neurons of vertebrates. Pflugers Arch 409(1–2):52–59

    Article  CAS  Google Scholar 

  • Takechi K, Carstens MI, Klein AH, Carstens E (2013) The antinoceptive and antihyperalgesic effects of topical propofol on dorsal horn neurons in the rat. Anesth Analg 116(4):932–938

    Article  CAS  Google Scholar 

  • Thiel G, Müller I, Rössler OG (2013) Signal transduction via TRPM3 channels in pancreatic β-cells. J Mol Endocrinol 50:R75–R83

    Article  CAS  Google Scholar 

  • Thut PD, Wrigley D, Gold MS (2003) Cold transduction in rat trigeminal ganglia neurons in vitro. Neuroscience 119(4):1071–1083

    Article  CAS  Google Scholar 

  • Todaka H, Taniguchi J, Satoh J, Mizuno A, Suzuki M (2004) Warm temperature-sensitive transient receptor potential vanilloid 4 (TRPV4) plays an essential role in thermal hyperalgesia. J Biol Chem 279(34):35133–35138

    Article  CAS  Google Scholar 

  • Trevisani M, Siemens J, Materazzi S, Bautista DM, Nassini R, Campi B, Imamachi N, Andre E, Patacchini R, Cottrell GS, Gatti R, Basbaum AI, Bunnett NW, Julius D, Geppetti P (2007) 4-hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci 104:13519–13524

    Article  CAS  Google Scholar 

  • Tsagareli MG, Tsiklauri N, Zanotto KL, Klein AH, Sawyer CM, Gurtskaia G, Abzianidze E, Carstens E (2010) Behavioral evidence of thermal hyperalgesia and mechanical allodynia induced by intradermal cinnamaldehyde in rats. Neurosci Lett 473(3):233–236

    Article  CAS  Google Scholar 

  • Ueda H, Inoue M, Yoshida A, Mizuno K, Yamamoto H, Marou J, Matsuno K, Mita S (2001) Metabotrophic neurosteroid/ς-receptor involved in stimulation of nociceptor endings of mice. J Pharmacol Exp Ther 298(2):703–710

    CAS  Google Scholar 

  • Urban MO, Zahn PK, Gebhart GF (1999) Descending facilitatory influences from the rostral medial medulla mediate secondary, but not primary hyperalgesia in the rat. Neuroscience 90:349–352

    Article  CAS  Google Scholar 

  • Ursu D, Knopp K, Beattie RE, Liu B, Sher E (2010) Pungency of TRPV1 agonists is directly correlated with kenetics of receptor activation and lipophilicity. Eur J Pharmacol 64(2–3):114–122

    Article  CAS  Google Scholar 

  • Vergnolle N, Cenac N, Altier C, Cellars L, Chapman K, Zamponi GW, Materazzi S, Nassini R, Liedtke W, Cattaruzza F, Grady EF, Geppetti P, Bunnett NW (2010) A role for transient receptor potential vanilloid 4 in tonicity-induced neurogenic inflammation. Br J Pharmacol 159(5):1161–1173

    Article  CAS  Google Scholar 

  • Vilceanu D, Stucky CL (2010) TRPA1 mediates mechanical currents in the plasma membrane of mouse sensory neurons. PLoS One 5(8):e12177

    Article  CAS  Google Scholar 

  • Voets T, Droogmans G, Wissenbach U, Janssens A, Flockerzi V, Nilius B (2004) The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature 430:748–754

    Article  CAS  Google Scholar 

  • Vogt-Eisele AK, Kerber K, Sherkheli MA, Vielhaber G, Panten J, Gisselmann G, Hatt H (2007) Monoterpenoid agonists of TRPV3. Br J Pharmacol 151:530–540

    Article  CAS  Google Scholar 

  • Vriens J, Watanabe H, Janssens A, Droogmans G, Voets T, Nilius B (2004) Cell swelling, heat and chemical agonists use distinct pathways for the activation of the cation channel TRPV4. Biophys J 86:128A

    Google Scholar 

  • Vriens J, Owsianik G, Hofmann T, Philipp SE, Stab J, Chen X, Benoit M, Xue F, Janssens A, Kerselaers S, Oberwinkler J, Vennekens R, Gudermann T, Nilius B, Voets T (2011) TRPM3 is a nociceptor channel involved in the detection of noxious heat. Neuron 70(3):482–494

    Article  CAS  Google Scholar 

  • Wagner TF, Loch S, Lambert S, Straub I, Mannebach S, Mathar I, Düfer M, Lis A, Flockerzi V, Philipp SE, Oberwinkler J (2008) Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic beta cells. Nat Cell Biol 10:1421–1430

    Article  CAS  Google Scholar 

  • Wasner G, Schattschneider J, Binder A, Baron R (2004) Topical menthol — a human model for cold pain by activation and sensitization of C nociceptors. Brain 127:1159–1171

    Article  Google Scholar 

  • Watanabe H, Vriens J, Suh SH, Benham CD, Droogmans G, Nilius B (2002) Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells. J Biol Chem 277:47044–47051

    Article  CAS  Google Scholar 

  • Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, Nilius B (2003) Anandamide and arachindonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424:434–438

    Article  CAS  Google Scholar 

  • Wei ET (1976) Chemical stimulants of shaking behaviour. J Pharm Pharmacol 28:722–724

    Article  CAS  Google Scholar 

  • Weng Y, Batista-Schepman PA, Barabas ME, Harris EQ, Dinsmore TB, Kossyreva EA, Foshage AM, Wang MH, Schwab MJ, Wang VM, Stucky CL, Story GM (2012) Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception. Mol Pain 8:75

    Article  CAS  Google Scholar 

  • Willis WD (2009) The role of TRPV1 receptors in pain evoked by noxious thermal and chemical stimuli. Exp Brain Res 196:5–11

    Article  CAS  Google Scholar 

  • Woodbury CJ, Zwick M, Wang SY, Lawson JJ, Caterina MJ, Koltzenburg M, Albers KM, Koerber HR, Davis BM (2004) Nociceptors lacking TRPV1 and TRPV2 have normal heat responses. J Neurosci 24:6410–6415

    Article  CAS  Google Scholar 

  • Xu H, Ramsey IS, Kotecha SA, Moran MM, Chong JA, Lawson D, Ge P, Lilly J, Silos-Santiago I, Xie Y, Distefano PS, Curtis R, Clapham DE (2002) TRPV3 is a calcium-permeable temperature-sensitive ion channel. Nature 418:181–186

    Article  CAS  Google Scholar 

  • Xu HX, Delling M, Jun JC, Clapham DE (2006) Oregano, thyme, and clove-derived flavors and skin sensitizers activate specific TRP channels. Nat Neurosci 9:628–635

    Article  CAS  Google Scholar 

  • Zamudio-Bulcock PA, Everett J, Harteneck C, Valenzuela CF (2011) Activation of steroid-sensitive TRPM3 channels potentiates glutamatergic transmission at cerebellar Purkinje neurons from developing rats. J Neurochem 119:474–485

    Article  CAS  Google Scholar 

  • Zanotto KL, Merrill AW, Iodi Carstens M, Carstens E (2007) Neurons in superficial trigeminal subnucleus caudalis responsive to oral cooling by menthol and other irritant stimuli. J Neurophysiol 97:966–978

    Article  CAS  Google Scholar 

  • Zimmermann K, Lennerz JK, Hein A, Link AS, Kaczmarek JS, Delling M, Uysal S, Pfeifer JD, Riccio A, Clapham DE (2011) Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system. Proc Natl Acad Sci USA 108(44):18114–18119

Download references

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflicts of interest. New results reported in this study were obtained with grant support from the National Institutes of Health (DE013685).

Animal studies reported in this manuscript were conducted under a protocol approved by the University of California, Davis, Institutional Animal Care and Use Committee.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Johns Hopkins University, Baltimore, MD, 21287, USA

    A. H. Klein

  2. Department of Neurobiology, Physiology, and Behavior, University of California, Davis, 1 Shields Avenue, Davis, CA, 95616, USA

    Minh Trannyguen, Christopher L. Joe, M. Iodi Carstens & E. Carstens

Authors
  1. A. H. Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Minh Trannyguen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher L. Joe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Iodi Carstens
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. Carstens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Carstens.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Klein, A.H., Trannyguen, M., Joe, C.L. et al. Thermosensitive Transient Receptor Potential (TRP) Channel Agonists and Their Role in Mechanical, Thermal and Nociceptive Sensations as Assessed Using Animal Models. Chem. Percept. 8, 96–108 (2015). https://doi.org/10.1007/s12078-015-9176-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12078-015-9176-9

Keywords

Search

Navigation