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 oxidants, including hydrogen peroxide (H2O2) and tert-butylhydroperoxide (tBHP) into the nape of the neck in mice and observed for 30 min. Results Intradermal H2O2 (0.03-1%) or tert-butylhydroperoxide (tBHP, 1-30 μmol) elicited robust scratching behavior, displaying an inverted-U-shaped dose-related curve. Naloxone, an opioid receptor antagonist, but not morphine, largely suppressed the oxidants-induced scratching. Chlorpheniramine, a histamine H1 receptor antagonist, blocked histamine but not oxidants-induced scratching, indicating the involvement of histamine-independent mechanism in oxidants-evoked itch. Further, resiniferatoxin (RTX) treatment abolished oxidants-induced scratching, suggesting an essential role of C-fibers. Notably, blockade of transient receptor potential subtype ankyryn 1 (TRPA1) by selective TRPA1 antagonist HC-030031, or genetic deletion of Trpa1 but not Trpv1 resulted in a profound reduction in H2O2-evoked scratching. Finally, systemic administration of the antioxidants N-acetyl-L-cysteine (NAC) or trolox (a water-soluble vitamin E analogue) attenuated scratching induced by the oxidants. Conclusion Oxidative stress by different oxidants can induce 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.

TRP Channels and Pruritus

“…Hydrogen peroxide induced itch was mediated by TRPA1 (as it was inhibited by the pharmacological blockade of TRPA1) but not by TRPV1, although the ablation of TRPV1+ neurons also abolished the itch response. The hydrogen peroxide induced itch was not influenced by histamine receptor blockers, which, similar to the above findings, further argue for the role of a TRPA1+ subpopulation within the TRPV1+ sensory afferent in the mediation of histamineindependent itch [323]. In addition, PAR2 activation was also reported to sensitize TRPA1 agonists-evoked currents in DRG neurons, likely via PLC mediated hydrolysis of PIP [324].…”

Potential New Therapeutic Targets for Pathological Pruritus

“…70) TRPA1 has been shown to be involved in oxidant-induced scratching. 71) Although the TRPA1 channel seems to be an interesting target for pruritus, it remains unknown whether it is involved in pathological pruritus.…”

Recent progress in understanding the mechanisms of pain and itch

“…Third, Ding et al reveal that a TRPC channel antagonist can alleviate inflammatory pain [11] . Furthermore, Liu and Ji present data showing that TRPA1 but not TRPV1 is required for oxidative stress-induced itch [8] . As well as peripheral sensitization, central sensitization is also covered in Tao's review, focusing on the inflammationinduced sensitization of spinal cord neurons, which is modulated by the trafficking of glutamatergic AMPA receptors [12] .…”

“…In another review, Liu and Ji propose a role of Toll-like receptors (e.g., TLR7), expressed by primary sensory neurons, in itch modulation [7] . Furthermore, they demonstrate that oxidative stress induces itching behavior (scratching) in mice, and this can be suppressed by antioxidants [8] .…”

“…Ten laboratories from China and the USA have contributed 11 papers to this special issue: 5 reviews and 6 full research articles [5][6][7][8][9][10][11][12][13][14][15] . This special issue aims to cover several areas of research in pain and itch, from peripheral to central mechanisms, and also from neuronal to glial mechanisms.…”