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Scratching behavior in mice induced by the proteinase-activated receptor-2 agonist, SLIGRL-NH2

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Abstract

We examined whether the proteinase-activated receptor-2 (PAR2) agonist, H-Ser-Leu-Ile-Gly-Arg-Leu-NH2 (SLIGRL-NH2), could induce scratching behavior in mice. Intradermal injections of SLIGRL-NH2 (10–50 μg) evoked dose dependent scratching. This behavior peaked near 5 min and returned to preinjection levels within 30 min. Pretreatment of animals with a histamine H1 receptor antagonist, pyrilamine, blocked histamine induced scratching, but it had little effect on SLIGRL scratching. Our study suggests that PAR2 mediates histamine independent itch.

Introduction

Proteinase-activated receptors (PAR) are a group of G-protein coupled receptors which are activated by cleavage of their terminal sequence by serine proteinases (Ossovskaya and Bunnett, 2003, Kawabata and Kuroda, 2000, Dery et al., 1998). The cleaved sequence remains tethered to the receptor and self-stimulates the receptor molecule. Some PARs can be activated with small peptides that duplicate the terminal sequence. In particular, the PAR2 subtypes are activated by trypsin and tryptase, and can be stimulated by the peptide, H-Ser-Leu-Ile-Gly-Arg-Leu-NH2 (SLIGRL-NH2) (Nystedt et al., 1994).

Early studies with cowhage, referred to as itching powder, demonstrated that itch produced by this substance was due to the proteinase, mucunain (Shelley and Arthur, 1955). Subsequently, other proteinases such as trypsin and tryptase have been shown to be puritogenic in humans (Steinhoff et al., 2003, Thomsen et al., 2002). The anatomical location of PAR2 in the sensory system, along with its activation by proteinases, suggests that PAR2 might be involved in itch. Thus, we examined scratching behavior in mice after administration of the murine PAR2 agonist peptide, SLIGRL-NH2, employing the methods outlined by Kuraishi et al. (1995). A further aim of this study was to determine the histamine dependence of SLIGRL-NH2 induced scratching by observing the effects of pretreatment with a histamine H1 receptor antagonist.

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Materials and methods

The Yale University Institutional Animal Care and Use Committee approved these protocols which conform to the European Community guidelines for the use of experimental animals. We used male CD-1 mice weighing 25–45 g (Charles River). They were allowed 1 week to acclimate to their new surroundings. Two days before experiments, a 1.5 cm diameter circular area was shaved at the back of the neck where intradermal injections (i.d.) were given. A small plastic chamber (9 × 9 × 13 cm) held a mouse during

Results

SLIGRL-NH2 caused dose-dependent scratching behavior in mice, which often began seconds after intradermal injection and subsided within 30 min (Fig. 1A). The “Sham” data showed that there is a certain amount of spontaneous scratching activity not related to i.d. injection. Although scratching was observed after injection of the saline vehicle, the amount of scratching was minimally above the spontaneous level. Analysis of total scratching in the 30 min after injection showed a significant

Discussion

Histamine often is the mediator of acute itch and amenable to treatment. However, a histamine mechanism is generally not the primary cause of pruritis in systemic, chronic conditions, such as atopic dermatitis (Steinhoff et al., 2003). These types of pruritis are resistant to antihistamines, which suggests the existence of histamine independent mediators of itch. For example, antihistamine can abolish pruritis induced by mast cell degranulation in controls but not in atopic dermatitis patients (

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