Thromboxane A2 Induces Itch-Associated Responses through TP Receptors in the Skin in Mice

Abstract

Thromboxane A2 (TXA2), a metabolite of arachidonic acid produced by cyclooxygenase and thromboxane synthase, is thought to participate in chronic dermatitis. This study investigated the involvement of TXA2 in cutaneous itch. An intradermal injection of U-46619, a stable analogue of TXA2, elicited scratching, an itch-associated response, in mice. Dose-response curve was bell shaped with a maximum effect at 10 nmol per site. The action of U-46619 was inhibited by a coinjection of the TP antagonist ONO-3708 and was abolished by TP receptor deficiency. TP receptor was mainly expressed in nerve fiber in the skin and keratinocytes. Thromboxane synthase was also expressed in keratinocytes. U-46619 increased intracellular Ca2+ ion concentration in primary cultures of dorsal root ganglion neurons and keratinocytes. The results suggest that TXA2 synthesized by keratinocytes acts as an itch mediator. It may elicit itch through the activation of TP receptors on primary afferents and keratinocytes; keratinocytes may produce itch mediators including TXA2. Thus, thromboxane synthase inhibitor and TP receptor antagonists will be candidates for antipruritic medicines.

The Role of Prostanoids in Atopic Dermatitis

“…Injection of a TP agonist alone elicited itch-associated responses. TP was expressed in both KCs and nerve fibers in skin (Andoh et al, 2007). TX synthase was also expressed in KCs.…”

“…Among these, mast cells have been found to be one of the major cellular sources of PGD 2 . TX synthase activity has been found in keratinocytes (Andoh et al, 2007) and high levels of TXB 2 , as a metabolite of TXA 2 , were detected in the cultured supernatant of LCs and DCs (Kabashima et al, 2003a). PGI 2 was detected in the skin of the murine AD model (Sugimoto et al, 2006).…”

“…In human studies, PGE 2 is a weak pruritogen and prolongs experimentally-induced itch (Hagermark and Strandberg, 1977;Neisius et al, 2002), although injection of PGE 2 alone does not elicit itch-associated response in animal experiments (Andoh and Kuraishi, 1998). TXA 2 is also reported as a mediator of itch (Andoh et al, 2007). Injection of a TP agonist alone elicited itch-associated responses.…”

Eicosanoids in skin inflammation

“…Finally, prostacyclin (PGI 2 ; detected as 6-keto-PGF 1α ) and TXA 2 (detected as TXB 2 ) have been found in whole skin extracts and cultured cells in vitro, albeit at low concentrations and it is possible that they may also be products of vascular endothelial cell or derive from infiltrating leukocytes [21,31]. IP and TP receptors have been identified in keratinocytes and other skin cells [24,52] and their prevalence has been linked to PGI 2 and TXA 2 signalling events accompanied cutaneous inflammatory and immune disorders [53,54].…”

TRP Channels and Pruritus

“…In addition, intradermal injection of other eicosanoids, such as leukotriene B4 (LTB4) or a nonhydrolysable thromboxan A2 analog evoked itch-associated responses in mice [116,117]. Furthermore, PAR2 activation on keratinocytes resulted in LTB4 (and PGE2) release in vitro and evoked scratching behavior in vivo which effects were reduced by 5-lipoxygenase inhibition arguing for that LTB4 may mediate the effect of PAR2 activation [118].…”