TRPA1 Mediates the Inflammatory Actions of Environmental Irritants and Proalgesic Agents

TRPA1 is an excitatory ion channel targeted by pungent irritants from mustard and garlic. TRPA1 has been proposed to function in diverse sensory processes, including thermal (cold) nociception, hearing, and inflammatory pain. Using TRPA1-deficient mice, we now show that this channel is the sole target through which mustard oil and garlic activate primary afferent nociceptors to produce inflammatory pain. TRPA1 is also targeted by environmental irritants, such as acrolein, that account for toxic and inflammatory actions of tear gas, vehicle exhaust, and metabolic byproducts of chemotherapeutic agents. TRPA1-deficient mice display normal cold sensitivity and unimpaired auditory function, suggesting that this channel is not required for the initial detection of noxious cold or sound. However, TRPA1-deficient mice exhibit pronounced deficits in bradykinin-evoked nociceptor excitation and pain hypersensitivity. Thus, TRPA1 is an important component of the transduction machinery through which environmental irritants and endogenous proalgesic agents depolarize nociceptors to elicit inflammatory pain.

[1]  P. Cesare,et al.  Ion channels gated by heat. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[2]  David E. Clapham,et al.  TRP channels as cellular sensors , 2003, Nature.

[3]  A I Basbaum,et al.  Impaired nociception and pain sensation in mice lacking the capsaicin receptor. , 2000, Science.

[4]  G. Leikauf,et al.  Bronchial responsiveness and inflammation in guinea pigs exposed to acrolein. , 1989, Journal of applied physiology.

[5]  S. Bevan,et al.  Anandamide-Evoked Activation of Vanilloid Receptor 1 Contributes to the Development of Bladder Hyperreflexia and Nociceptive Transmission to Spinal Dorsal Horn Neurons in Cystitis , 2004, The Journal of Neuroscience.

[6]  R. Tjeerdema,et al.  Fate and effects of acrolein. , 1995, Reviews of environmental contamination and toxicology.

[7]  T. Yaksh,et al.  Quantitative assessment of tactile allodynia in the rat paw , 1994, Journal of Neuroscience Methods.

[8]  Yi Dai,et al.  Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with aδ/c‐fibers and colocalization with trk receptors , 2005, The Journal of comparative neurology.

[9]  Z. Handzel.  Effects of Environmental Pollutants on Airways, Allergic Inflammation, and the Immune Response , 2000, Reviews on environmental health.

[10]  N. Herrig,et al.  Synthetic smoke with acrolein but not HCl produces pulmonary edema. , 1988, Journal of applied physiology.

[11]  N. Sakura,et al.  Monitoring of urinary acrolein concentration in patients receiving cyclophosphamide and ifosphamide. , 2004, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[12]  Lack of role for the vanilloid receptor in response to several inspired irritant air pollutants in the C57Bl/6J mouse , 2004, Neuroscience Letters.

[13]  J. Laird,et al.  Allodynia and hyperalgesia evoked by sciatic mononeuropathy in NK1 receptor knockout mice , 2000, Neuroreport.

[14]  A. Basbaum,et al.  Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition , 2001, Nature.

[15]  Stephen B. McMahon,et al.  Inflammatory mediators and modulators of pain , 2005 .

[16]  A. Ahluwalia,et al.  Characterization of the capsaicin‐sensitive component of cyclophosphamide‐induced inflammation in the rat urinary bladder , 1994, British journal of pharmacology.

[17]  A. Basbaum,et al.  Molecular mechanisms of nociception , 2001, Nature.

[18]  D. McKemy,et al.  Lessons from peppers and peppermint: the molecular logic of thermosensation , 2003, Current Opinion in Neurobiology.

[19]  C. Montell,et al.  The TRP Channels, a Remarkably Functional Family , 2002, Cell.

[20]  R. Fleming.  An Overview of Cyclophosphamide and Ifosfamide Pharmacology , 1997, Pharmacotherapy.

[21]  D. Nicol.  Cyclophosphamide and the urinary tract , 2002, Internal medicine journal.

[22]  C. Maggi,et al.  Cyclophosphamide cystitis in rats: involvement of capsaicin-sensitive primary afferents. , 1992, Journal of the autonomic nervous system.

[23]  L. Premkumar,et al.  Induction of vanilloid receptor channel activity by protein kinase C , 2000, Nature.

[24]  G. Leikauf.  Hazardous air pollutants and asthma. , 2002, Environmental health perspectives.

[25]  P. Cox.  Cyclophosphamide cystitis--identification of acrolein as the causative agent. , 1979, Biochemical pharmacology.

[26]  Olov Sterner,et al.  Pungent products from garlic activate the sensory ion channel TRPA1. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Kollarik,et al.  Activation of bronchopulmonary vagal afferent nerves with bradykinin, acid and vanilloid receptor agonists in wild‐type and TRPV1–/– mice , 2004, The Journal of physiology.

[28]  P. Cesare,et al.  A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[29]  S. Bingham,et al.  Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia , 2000, Nature.

[30]  K. Nagata,et al.  Nociceptor and Hair Cell Transducer Properties of TRPA1, a Channel for Pain and Hearing , 2005, The Journal of Neuroscience.

[31]  J. Stanek,et al.  Sensory nerve-mediated immediate nasal responses to inspired acrolein. , 1999, Journal of applied physiology.

[32]  J. Polak,et al.  Acrolein depletes the neuropeptides CGRP and substance P in sensory nerves in rat respiratory tract. , 1990, Environmental health perspectives.

[33]  D. McKemy,et al.  Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1 , 2004, Nature.

[34]  Y. Namkung,et al.  Null Mutation of α1D Ca2+ Channel Gene Results in Deafness but No Vestibular Defect in Mice , 2004, Journal of the Association for Research in Otolaryngology.

[35]  A. Dray,et al.  Bradykinin and inflammatory pain , 1993, Trends in Neurosciences.

[36]  Peter McIntyre,et al.  ANKTM1, a TRP-like Channel Expressed in Nociceptive Neurons, Is Activated by Cold Temperatures , 2003, Cell.

[37]  A. Patapoutian,et al.  The Pungency of Garlic: Activation of TRPA1 and TRPV1 in Response to Allicin , 2005, Current Biology.

[38]  D. Julius,et al.  A capsaicin-receptor homologue with a high threshold for noxious heat , 1999, Nature.

[39]  M. Carr,et al.  Pharmacology of airway afferent nerve activity , 2001, Respiratory research.

[40]  A. Patapoutian,et al.  Noxious Cold Ion Channel TRPA1 Is Activated by Pungent Compounds and Bradykinin , 2004, Neuron.

[41]  E. Christian,et al.  Protective role for neuropeptides in acute pulmonary response to acrolein in guinea pigs. , 1993, Journal of applied physiology.

[42]  Peter Goodfellow,et al.  "Male Development of Chromosomally Female Mice Transgenic for Sry gene" (1991), by Peter Koopman, et al. , 2014 .

[43]  J. Greer,et al.  Targeting genes for self-excision in the germ line. , 1999, Genes & development.

[44]  Heidi L. Rehm,et al.  TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells , 2004, Nature.

[45]  M. Flonta,et al.  Ion channels activated by cold and menthol in cultured rat dorsal root ganglion neurones , 2002, Neuroscience Letters.

[46]  B. Bryant,et al.  Multiple types of sensory neurons respond to irritating volatile organic compounds (VOCs): Calcium fluorimetry of trigeminal ganglion neurons , 2005, Pain.

[47]  Gordon Reid,et al.  ThermoTRP channels and cold sensing: what are they really up to? , 2005, Pflügers Archiv.

[48]  S. Musto,et al.  Smoke aldehyde component influences pulmonary edema. , 1992, Journal of applied physiology.

[49]  H. Rang,et al.  Bradykinin‐induced depolarization of primary afferent nerve terminals in the neonatal rat spinal cord in vitro , 1990, British journal of pharmacology.

[50]  P. Wall,et al.  Textbook of pain , 1989 .

[51]  D. McKemy,et al.  Identification of a cold receptor reveals a general role for TRP channels in thermosensation , 2002, Nature.

[52]  R. Dubner,et al.  A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia , 1987, Pain.

[53]  C. Woolf,et al.  Pain TRPs , 2005, Neuron.