Superoxide generation and leukocyte accumulation: key elements in the mediation of leukotriene B₄‐induced itch by transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1

Abstract

The underlying mechanisms of itch are poorly understood. We have investigated a model involving the chemoattractant leukotriene B₄ (LTB₄) that is up-regulated in common skin diseases. Intradermal injection of LTB4 (0.1 nmol/site) into female CD1 mice induced significant scratching movements (used as an itch index) compared with vehicle-injected (0.1% bovine serum albumin-saline) mice. Intraperitoneal transient receptor potential (TRP) channel antagonist treatment significantly inhibited itch as follows: TRP vanilloid 1 (TRPV1) antagonist SB366791 (0.5 mg/kg, by 97%) and the TRP ankyrin 1 (TRPA1) antagonists TCS 5861528 (10 mg/kg; 82%) and HC-030031 (100 mg/kg; 76%). Leukotriene B₄ receptor 2 antagonism by LY255283 (5 mg/kg i.p.; 62%) reduced itch. Neither TRPV1-knockout (TRPV1-KO) nor TRPA1-knockout (TRPA1-KO mice exhibited LTB₄-induced itch compared with their wild-type counterparts. The reactive oxygen species scavengers N-acetylcysteine (NAC; 204 mg/kg i.p.; 86%) or superoxide dismutase (SOD; 10 mg/kg i.p.; 83%) also inhibited itch. LTB4-induced superoxide release was attenuated by TCS 5861528 (56%) and HC-030031 (66%), NAC (58%), SOD (50%), and LY255283 (59%) but not by the leukotriene B4 receptor 1 antagonist U-75302 (9 nmol/site) or SB366791. Itch, superoxide, and myeloperoxidase generation were inhibited by the leukocyte migration inhibitor fucoidan (10 mg/kg i.v.) by 80, 61, and 34%, respectively. Myeloperoxidase activity was also reduced by SB366791 (35%) and SOD (28%). TRPV1-KO mice showed impaired myeloperoxidase release, whereas TRPA1-KO mice exhibited diminished production of superoxide. This result provides novel evidence that TRPA1 and TRPV1 contribute to itch via distinct mechanisms.

Leukotrienes orchestrating allergic skin inflammation

“…Furthermore, it is in line with the recent finding of LTB 4 as the critical mediator instigating 'swarm-like' behaviour of neutrophils, that is, the rapid migration of high numbers of neutrophils to inflammatory foci in a closed formation within peripheral tissues (39). Notably, skin scratching was suggested to precipitate skin lesions in AD patients (40), and LTB 4 is an important mediator that induces the sensation of itching in mice (41,42). Hence, a vicious circle of scratching ?…”

A Mouse Model of Peripheral Postischemic Dysesthesia: Involvement of Reperfusion-Induced Oxidative Stress and TRPA1 Channel

“…HC-030031 is a potent and selective TRPA1 channel blocker and has been used as a tool for investigating the role of TRPA1 channel in both in vitro and in vivo experiments (McNamara et al, 2007;Fernandes et al, 2013). To determine whether TRPA1 channels are involved in postischemic licking, we investigated the effect of HC-030031.…”

“…Several lines of evidence suggest that ROS are involved in mechanical and thermal hypersensitivities under inflammatory and neuropathic conditions (Keeble et al, 2009;Fidanboylu et al, 2011). In addition, ROS generation has been shown to be involved in itch-related response induced by intradermal injection of leukotriene B 4 (Fernandes et al, 2013). ROS may be associated with a variety of pathologic cutaneous sensations.…”

Potential New Therapeutic Targets for Pathological Pruritus

“…42) When LTB 4 is produced in the dermis (e.g., mast cells), it may act as a leukocyte chemoattractant via BLT 2 receptor stimulation, and leukocytereleased superoxide may induce itching. 43) Nonselective LTB 4 antagonists are more desirable than the selective BLT 1 or BLT 2 antagonists because both BLT 1 and BLT 2 receptors can be involved in LTB 4 -mediated itching. A 5-lipoxygenase inhibitor relieves pruritus in Sjögren-Larsson syndrome 44) and has a tendency to improve pruritus in atopic dermatitis.…”