Pharmacological Characterization of Itch-Associated Response Induced by Repeated Application of Oxazolone in Mice

Abstract

Abstract. We investigated pharmacological characteristics of the itch-associated response to chronic dermatitis induced by 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (oxazolone) repeated application in mice. Application of an oxazolone challenge to mice with oxazolone-induced chronic dermatitis evoked severe and transient scratching behavior for up to 1h. Thereafter, mild and continuous scratching behavior was observed for at least 8 h. Both severe and continuous scratching behaviors were suppressed by the opioid-receptor antagonist naltrexone, but not by the H 1 histamine-receptor antagonist fexofenadine, 5-hydroxytryptamine-2 (5-HT 2 )-receptor antagonist methysergide, NK 1 -receptor antagonist LY303870, cyclooxygenase inhibitor indomethacin, or the platelet-activating factor-receptor antagonist YM264. The severe scratching behavior was suppressed by the 5-lipoxygenase inhibitor zileuton and leukotriene B 4 -receptor antagonist ONO-4057, but not by the cysteinyl leukotriene-receptor antagonist montelukast. The continuous scratching behavior was suppressed by pretreatment with the non-selective muscarinic acetylcholine-receptor antagonist atropine and M 3 muscarinic acetylcholine-receptor antagonist darifenacin. These results suggest that leukotriene B 4 receptor and M 3 muscarinic acetylcholine receptor are involved in the itch-associated response induced by repeated application of oxazolone in mice.

Potential New Therapeutic Targets for Pathological Pruritus

“…3,37) LTB 4 was shown to be involved in scratching in mice with chronic allergic dermatitis and allergic conjunctivitis, 3,32,38) but not in those with acute cutaneous allergy. 39) There are two LTB 4 receptor subtypes, BLT 1 and BLT 2 , which have high and low binding affinities for LTB 4 , respectively.…”

Gabapentin and Pregabalin Inhibit the Itch-Associated Response Induced by the Repeated Application of Oxazolone in Mice

“…In our previous study, we demonstrated that the scratching behavior in this model was suppressed by an opioid receptor antagonist, suggesting that this behavior is an itch-associated response (12). Gabapentin and pregabalin have previ- ously been reported to have an anti-nociceptive action in neuropathic pain models (16 -18).…”

“…We recently reported that mice that received repeated applications of oxazolone showed an antigen-induced severe scratching behavior, followed by chronic dermatitis-induced continuous scratching behavior (12). We have also shown that these mice respond similarly to human patients in terms of the therapeutic activity of anti-itch drugs.…”

“…We have also shown that these mice respond similarly to human patients in terms of the therapeutic activity of anti-itch drugs. This suggests that the mechanism(s) responsible for producing the scratching in mice after repeated application with oxazolone resembles that of the itching in patients with atopic dermatitis (12).…”

The cannabinoid receptor-2 is involved in allergic inflammation

“…Moreover, the magnitude of the acanthosis induced by repeated applications of OXA in the CB2-KO mice was significantly reduced compared with WT mice. It has been reported that repeated application of OXA is associated with increased immunoglobulin-E (IgE) in serum and Th2 cytokines at the site of dermatitis (Kitagaki et al, 1995;Tsukumo et al, 2010). Taniguchi et al (2007) had reported that the pinna acanthosis was accompanied by an increase in the amount of epithelium, over-expression of the nerve growth factor (NGF) in the epithelium, and cuticle expression of the p75-positive fiber that plays a role in epithelial thickening.…”