title: Oxidative stress induces itch via activation of transient receptor potential subtype ankyrin 1 in mice.
abstract: OBJECTIVE
  To investigate the role of oxidative stress in itch-indicative scratching behavior in mice, and furthermore, to define the cellular and molecular mechanisms underlying oxidative stress-mediated itch.
  
  
  METHODS
  Scratching behavior was induced by intradermal injection of the oxidants hydrogen peroxide (H₂O₂) or tert-butylhydroperoxide (tBHP) into the nape of the neck in mice. The mice were observed for 30 min.
  
  
  RESULTS
  Intradermal H₂O₂ (0.03%-1%) or tBHP (1-30 μmol) elicited robust scratching behavior, displaying an inverted U-shaped dose-response curve. Naloxone, an opioid receptor antagonist, but not morphine, largely suppressed the oxidant-induced scratching. Chlorpheniramine, a histamine H1 receptor antagonist, blocked histamine- but not oxidant-induced scratching, indicating the involvement of a histamine-independent mechanism in oxidant-evoked itch. Further, resiniferatoxin treatment abolished oxidant-induced scratching, suggesting an essential role of C-fibers. Notably, blockade of transient receptor potential subtype ankyrin 1 (TRPA1) with the selective TRPA1 antagonist HC-030031, or genetic deletion of Trpa1 but not Trpv1 (subfamily V, member 1) resulted in a profound reduction in H₂O₂-evoked scratching. Finally, systemic administration of the antioxidant N-acetyl-L-cysteine or trolox (a water-soluble vitamin E analog) attenuated scratching induced by the oxidants.
  
  
  CONCLUSIONS
  Oxidative stress by different oxidants induces profound scratching behavior, which is largely histamine- and TRPV1-independent but TRPA1-dependent. Antioxidants and TRPA1 antagonists may be used to treat human itch conditions associated with oxidative stress.
authors.affiliation: Sensory Plasticity Laboratory, Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. tliu5@partners.org
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D004195:Disease Models, Animal; D007509:Irritants / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011537:Pruritus / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D000975:Antioxidants; D007509:Irritants; D016877:Oxidants; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse