Leukotriene B4 Mediates Sphingosylphosphorylcholine-Induced Itch-Associated Responses in Mouse Skin

Abstract

In atopic dermatitis, the concentration in the skin of sphingosylphosphorylcholine (SPC), which is produced from sphingomyelin by sphingomyelin deacylase, is increased. In the present study, we investigated the itch-eliciting activity of SPC and related substances and the mechanisms of SPC action in mice. An intradermal injection of SPC, but not sphingomyelin and sphingosine, induced scratching, an itch-associated response, which was not suppressed by a deficiency in mast cells or the H(1) histamine receptor antagonist terfenadine. The action of SPC was inhibited by the mu-opioid receptor antagonist naltrexone. SPC action also was inhibited by the 5-lipoxygenase inhibitor zileuton and the leukotriene B(4) antagonist ONO-4057, but not by the cyclooxygenase inhibitor indomethacin. Moreover, SPC action was inhibited by the antiallergic agent azelastine, which suppresses the action and production of leukotriene B(4). Administration of SPC to the skin and to primary cultures of keratinocytes increased leukotriene B(4) production. SPC increased intracellular Ca(2+) ion concentration in primary cultures of dorsal root ganglion neurons and keratinocytes. These results suggest that SPC induces itching through a direct action on primary afferents and leukotriene B(4) production of keratinocytes. Sphingomyelin deacylase and SPC receptors may be previously unreported targets for antipruritic drugs.

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

“…However, the role of leukotrienes or prostaglandins in chronic dermatitis induced by repeated application of oxazolone is unclear so far. It has been reported that the 5-lipoxygenase inhibitor zileuton and the 5-lipoxygenase activating protein inhibitor MK-866 suppress itchassociated behavior induced by several pruritogens in mice (15,35,36). Furthermore, the oxazolone-induced severe scratching behavior was completely suppressed by pretreatment with zileuton, but not the cyclooxygenase inhibitor indomethacin or the platelet-activating factor-receptor antagonist YM264.…”

Potential New Therapeutic Targets for Pathological Pruritus

“…32) Intradermal injection of SPc, but not of sphingomyelin and sphingosine, elicits scratching in mice. [32][33][34] SPc may act on the epidermal keratinocytes, dendritic cells, primary sensory neurons, and mast cells in the skin. [34][35][36] Naturally occurring d-erythro SPc, but not l-threo SPc, induces scratching after intradermal injection, raising the possibility that SPC acts on a specific receptor to induce itching.…”

“…[32][33][34] SPc may act on the epidermal keratinocytes, dendritic cells, primary sensory neurons, and mast cells in the skin. [34][35][36] Naturally occurring d-erythro SPc, but not l-threo SPc, induces scratching after intradermal injection, raising the possibility that SPC acts on a specific receptor to induce itching. 33) However, SPc receptors remain unclear, although some candidates were reported.…”

Methods for Preclinical Assessment of Antipruritic Agents and Itch Mechanisms Independent of Mast-Cell Histamine

“…17,23,27) In healthy humans, naloxone increases itch thresholds to histamine. 18) In contrast, µ-opioid receptor agonists elicit facial scratching following intracisternal injection and body scratch- ; the failure of histamine to elicit scratching in mice (1974) 8) ; scratching induced by intracerebroventricular and intrathecal injections of bombesin in rats (1983); responses of primary afferents to cowhage stimulation in cats (1987) 10,11) ; scratching induced by injections of opioids into the medullary dorsal horn in monkeys (1992,1993); and scratching induced by injection of morphine into the medullary dorsal horn in rats (1995).…”

“…Leukotriene B 4 is involved in the scratchinducing actions of other keratinocyte-producing substances such as sphingosylphosphorylcholine and nociceptin 27,114) (Fig. 4).…”