Top

Published in:

Open Access 01-12-2007 | Research

A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition

Authors: Matt Petrus, Andrea M Peier, Michael Bandell, Sun Wook Hwang, Truc Huynh, Nicholas Olney, Tim Jegla, Ardem Patapoutian

Published in: Molecular Pain | Issue 1/2007

Abstract

Mechanical hyperalgesia is a clinically-relevant form of pain sensitization that develops through largely unknown mechanisms. TRPA1, a Transient Receptor Potential ion channel, is a sensor of pungent chemicals that may play a role in acute noxious mechanosensation and cold thermosensation. We have developed a specific small molecule TRPA1 inhibitor (AP18) that can reduce cinnameldehyde-induced nociception in vivo. Interestingly, AP18 is capable of reversing CFA-induced mechanical hyperalgesia in mice. Although TRPA1-deficient mice develop normal CFA-induced hyperalgeisa, AP18 is ineffective in the knockout mice, consistent with an on-target mechanism. Therefore, TRPA1 plays a role in sensitization of nociception, and that compensation in TRPA1-deficient mice masks this requirement.

Available only for authorised users

Woolf CJ, Ma Q: Nociceptors-noxious stimulus detectors. Neuron 2007,55(3):353–364. 10.1016/j.neuron.2007.07.016PubMedCrossRef

Ossipov MH, Lai J, Malan TP Jr., Porreca F: Spinal and supraspinal mechanisms of neuropathic pain. Ann N Y Acad Sci 2000, 909: 12–24.PubMedCrossRef

Woolf CJ: Dissecting out mechanisms responsible for peripheral neuropathic pain: implications for diagnosis and therapy. Life Sci 2004,74(21):2605–2610. 10.1016/j.lfs.2004.01.003PubMedCrossRef

Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D: The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997,389(6653):816–824. 10.1038/39807PubMedCrossRef

Bhave G, Gereau RW: Posttranslational mechanisms of peripheral sensitization. J Neurobiol 2004,61(1):88–106. 10.1002/neu.20083PubMedCrossRef

Hucho T, Levine JD: Signaling pathways in sensitization: toward a nociceptor cell biology. Neuron 2007,55(3):365–376. 10.1016/j.neuron.2007.07.008PubMedCrossRef

Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D: Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000,288(5464):306–313. 10.1126/science.288.5464.306PubMedCrossRef

Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, Harries MH, Latcham J, Clapham C, Atkinson K, Hughes SA, Rance K, Grau E, Harper AJ, Pugh PL, Rogers DC, Bingham S, Randall A, Sheardown SA: Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 2000,405(6783):183–187. 10.1038/35012076PubMedCrossRef

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: ANKTM1, a TRP-like Channel Expressed in Nociceptive Neurons, Is Activated by Cold Temperatures. Cell 2003,112(6):819–829. 10.1016/S0092-8674(03)00158-2PubMedCrossRef

10.

Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, Patapoutian A: Noxious Cold Ion Channel TRPA1 Is Activated by Pungent Compounds and Bradykinin. Neuron 2004,41(6):849–857. 10.1016/S0896-6273(04)00150-3PubMedCrossRef

11.

Macpherson LJ, Dubin AE, Evans MJ, Marr F, Schultz PG, Cravatt BF, Patapoutian A: Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature 2007,445(7127):541–545. 10.1038/nature05544PubMedCrossRef

12.

Hinman A, Chuang HH, Bautista DM, Julius D: TRP channel activation by reversible covalent modification. Proc Natl Acad Sci U S A 2006,103(51):19564–19568. 10.1073/pnas.0609598103PubMedCentralPubMedCrossRef

13.

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: 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A 2007,104(33):13519–13524. 10.1073/pnas.0705923104PubMedCentralPubMedCrossRef

14.

McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL, Zhao M, Hayward NJ, Chong JA, Julius D, Moran MM, Fanger CM: TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci U S A 2007,104(33):13525–13530. 10.1073/pnas.0705924104PubMedCentralPubMedCrossRef

15.

Macpherson LJ, Xiao B, Kwan KY, Petrus MJ, Dubin AE, Hwang S, Cravatt B, Corey DP, Patapoutian A: An ion channel essential for sensing chemical damage. J Neurosci 2007,27(42):11412–11415. 10.1523/JNEUROSCI.3600-07.2007PubMedCrossRef

16.

Kwan KY Allchorne, A.J., Vollrath, M.A., Christensen, A., Zhang, D.S., Woolf, C. J., Corey, D. P.: TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron 2006.,50(2):

17.

Bautista DM, Jordt SE, Nikai T, Tsuruda PR, Read AJ, Poblete J, Yamoah EN, Basbaum AI, Julius D: TRPA1 Mediates the Inflammatory Actions of Environmental Irritants and Proalgesic Agents. Cell 2006,124(6):1269–1282. 10.1016/j.cell.2006.02.023PubMedCrossRef

18.

Macpherson LJ, Hwang SW, Miyamoto T, Dubin AE, Patapoutian A, Story GM: More than cool: Promiscuous relationships of menthol and other sensory compounds. Mol Cell Neurosci 2006,32(4):335–343. 10.1016/j.mcn.2006.05.005PubMedCrossRef

19.

Sawada Y, Hosokawa H, Hori A, Matsumura K, Kobayashi S: Cold sensitivity of recombinant TRPA1 channels. Brain Res 2007, 1160: 39–46. 10.1016/j.brainres.2007.05.047PubMedCrossRef

20.

Dhaka A, Viswanath V, Patapoutian A: TRP Ion Channels and Temperature Sensation. Annu Rev Neurosci 2006.

21.

Obata K, Katsura H, Mizushima T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Tokunaga A, Tominaga M, Noguchi K: TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. J Clin Invest 2005,115(9):2393–2401. 10.1172/JCI25437PubMedCentralPubMedCrossRef

22.

Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, Julius D: Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 2004,427(6971):260–265. 10.1038/nature02282PubMedCrossRef

23.

Steiner AA, Turek VF, Almeida MC, Burmeister JJ, Oliveira DL, Roberts JL, Bannon AW, Norman MH, Louis JC, Treanor JJ, Gavva NR, Romanovsky AA: Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors. J Neurosci 2007,27(28):7459–7468. 10.1523/JNEUROSCI.1483-07.2007PubMedCrossRef

24.

Gavva NR, Bannon AW, Surapaneni S, Hovland DN Jr., Lehto SG, Gore A, Juan T, Deng H, Han B, Klionsky L, Kuang R, Le A, Tamir R, Wang J, Youngblood B, Zhu D, Norman MH, Magal E, Treanor JJ, Louis JC: The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation. J Neurosci 2007,27(13):3366–3374. 10.1523/JNEUROSCI.4833-06.2007PubMedCrossRef

25.

Ruparel NB, Patwardhan AM, Akopian AN, Hargreaves KM: Homologous and heterologous desensitization of capsaicin and mustard oil responses utilize different cellular pathways in nociceptors. Pain 2007.

26.

Alessandri-Haber N, Dina OA, Joseph EK, Reichling D, Levine JD: A transient receptor potential vanilloid 4-dependent mechanism of hyperalgesia is engaged by concerted action of inflammatory mediators. J Neurosci 2006,26(14):3864–3874. 10.1523/JNEUROSCI.5385-05.2006PubMedCrossRef

27.

Chung MK, Lee H, Mizuno A, Suzuki M, Caterina MJ: TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. J Biol Chem 2004,279(20):21569–21575. 10.1074/jbc.M401872200PubMedCrossRef

28.

Diogenes A, Akopian AN, Hargreaves KM: NGF up-regulates TRPA1: implications for orofacial pain. J Dent Res 2007,86(6):550–555.PubMedCrossRef

29.

Dai Y, Wang S, Tominaga M, Yamamoto S, Fukuoka T, Higashi T, Kobayashi K, Obata K, Yamanaka H, Noguchi K: Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. J Clin Invest 2007,117(7):1979–1987. 10.1172/JCI30951PubMedCentralPubMedCrossRef

30.

Christensen AP, Corey DP: TRP channels in mechanosensation: direct or indirect activation? Nat Rev Neurosci 2007,8(7):510–521. 10.1038/nrn2149PubMedCrossRef

31.

Zurborg S, Yurgionas B, Jira JA, Caspani O, Heppenstall PA: Direct activation of the ion channel TRPA1 by Ca(2+). Nat Neurosci 2007.

32.

Kindt KS, Viswanath V, Macpherson L, Quast K, Hu H, Patapoutian A, Schafer WR: Caenorhabditis elegans TRPA-1 functions in mechanosensation. Nat Neurosci 2007,10(5):568–577. 10.1038/nn1886PubMedCrossRef

33.

Jegla T, Salkoff L: A novel subunit for shal K+ channels radically alters activation and inactivation. J Neurosci 1997,17(1):32–44.PubMed

34.

Moqrich A, Hwang SW, Earley TJ, Petrus MJ, Murray AN, Spencer KS, Andahazy M, Story GM, Patapoutian A: Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 2005,307(5714):1468–1472. 10.1126/science.1108609PubMedCrossRef

35.

Cao YQ, Mantyh PW, Carlson EJ, Gillespie AM, Epstein CJ, Basbaum AI: Primary afferent tachykinins are required to experience moderate to intense pain. Nature 1998,392(6674):390–394. 10.1038/32897PubMedCrossRef

Title: A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition
Authors: Matt Petrus
Andrea M Peier
Michael Bandell
Sun Wook Hwang
Truc Huynh
Nicholas Olney
Tim Jegla
Ardem Patapoutian
Publication date: 01-12-2007
Publisher: BioMed Central
Published in: Molecular Pain / Issue 1/2007
Electronic ISSN: 1744-8069
DOI: https://doi.org/10.1186/1744-8069-3-40

Keynote webinar | Spotlight on medication adherence

Springer Medicine

A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2007

Phosphorylation of ERK in neurokinin 1 receptor-expressing neurons in laminae III and IV of the rat spinal dorsal horn following noxious stimulation

Pain-related anxiety-like behavior requires CRF1 receptors in the amygdala

Spinal NKCC1 blockade inhibits TRPV1-dependent referred allodynia

Inward currents induced by ischemia in rat spinal cord dorsal horn neurons

Inactivation properties of sodium channel Nav1.8 maintain action potential amplitude in small DRG neurons in the context of depolarization

Roles of TRPV1 and neuropeptidergic receptors in dorsal root reflex-mediated neurogenic inflammation induced by intradermal injection of capsaicin