Activation of Proteinase-Activated Receptors Induces Itch-Associated Response Through Histamine-Dependent and -Independent Pathways in Mice

Tsujii, Kenichiro; Andoh, Tsugunobu; Lee, Jung‐Bum; Kuraishi, Yasushi

doi:10.1254/jphs.08200sc

Cited by 50 publications

(58 citation statements)

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“…In contrast to NC mice, ICR mice show slight scratching in response to activating peptides of PAR 1 and PAR 4 , but the responses to PAR 1 -and PAR 4 -, but not PAR 2 -, activating peptides, were suppressed by the H 1 histamine-receptor antagonist, suggesting that the PAR 1 and PAR 4 responses are mediated by histamine released from mast cells (8). An intradermal injection of histamine elicits scratching in ICR mice, but not in NC mice (10,14,15).…”

Section: Discussionmentioning

confidence: 77%

“…Therefore, the activation of PAR 1 and PAR 4 could cause the degranulation of mast cells to release histamine, but even so, they might not elicit scratching in NC mice. Since intradermal injections of PAR 1 -and PAR 4 -activating peptides may degranulate mast cells (8), these peptides were predicted to release mast cell tryptase to elicit scratching in healthy NC mice. However, they did not elicit scratching in healthy NC mice at a dose (100 nmol/site) eliciting scratching in ICR mice (8).…”

Section: Discussionmentioning

confidence: 99%

“…Activating peptides of PAR 1 and PAR 4 , but not PAR 3 , also elicit scratching, but scratching induced by PAR 1 -and PAR 4 -activating, but not PAR 2 -activating, peptides is inhibited by an H 1 histamine-receptor antagonist, suggesting that PAR 1 -and PAR 4 -associated scratching involves histamine release from mast cells (8). Thus, it is interesting to investigate whether tryptase and PAR subtypes are involved in the itching of chronic dermatitis.…”

Section: Introductionmentioning

confidence: 97%

“…Intradermal injection of PAR 2 -activating peptide elicits scratching in mice (7,8). Activating peptides of PAR 1 and PAR 4 , but not PAR 3 , also elicit scratching, but scratching induced by PAR 1 -and PAR 4 -activating, but not PAR 2 -activating, peptides is inhibited by an H 1 histamine-receptor antagonist, suggesting that PAR 1 -and PAR 4 -associated scratching involves histamine release from mast cells (8).…”

Section: Introductionmentioning

confidence: 98%

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Involvement of Tryptase and Proteinase-Activated Receptor-2 in Spontaneous Itch-Associated Response in Mice With Atopy-like Dermatitis

Tsujii

Andoh

et al. 2009

J Pharmacol Sci

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Abstract. This study investigated the involvement of tryptase and proteinase-activated receptor (PAR) subtypes in spontaneous scratching, an itch-associated behavior, in NC mice. This strain of mice showed chronic atopy-like dermatitis and severe spontaneous scratching, when kept a long time in a conventional environment. The trypsin-like serine proteinase inhibitor nafamostat mesilate (1 -10 mg/kg) dose-dependently inhibited spontaneous scratching in mice with dermatitis. The activity of tryptase was increased in the lesional skin, which was inhibited by nafamostat at a dose inhibiting spontaneous scratching. Enzyme histochemistry revealed the marked increase of toluidine blue-stained cells, probably mast cells, with tryptase activity in the dermis of the lesional skin. Intravenous injection of anti-PAR 2 antibody suppressed spontaneous scratching of mice with dermatitis. Intradermal injection of the PAR 2 -activating peptide SLI-GRL-NH 2 , but not PAR 1 , 3 , 4 -activating peptides, elicited scratching at doses of 10 -100 nmol/site in healthy mice. PAR 2 -immunoreactivity was observed in the epidermal keratinocytes in healthy and dermatitis mice. These results suggest that PAR 2 and serine proteinase(s), mainly tryptase, are involved in the itch of chronic dermatitis.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Involvement of Tryptase and Proteinase-Activated Receptor-2 in Spontaneous Itch-Associated Response in Mice With Atopy-like Dermatitis

Tsujii

Andoh

et al. 2009

J Pharmacol Sci

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“…A range of mediators, such as histamine [3], prostaglandins [4], serotonin [5], bradykinin [6], cytokines [7], endothelin-1 [8], leukotrienes [9], proteases [10,11], neuropeptides [12] and opioids [13] orchestrate this response by acting on their receptors located on the nerve terminals. Pruritus (scratching behavior) is also a common symptom that results from insect bites, and can be experimentally induced in animals by the intradermal (i.d.)…”

Section: Introductionmentioning

confidence: 99%

Protective effects of exogenous and endogenous hydrogen sulfide in mast cell-mediated pruritus and cutaneous acute inflammation in mice

Rodrigues

Ekundi-Valentim

Florenzano

et al. 2017

Pharmacological Research

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Protective effects of exogenous and endogenous hydrogen sulfide in mast cell-mediated pruritus and cutaneous acute inflammation in mice.Pharmacological Research http://dx.doi.org/10. 1016/j.phrs.2016.11.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Graphical abstract RESEARCH PAPER ABSTRACTThe recently described 'gasomediator' hydrogen sulfide (H2S) has been involved in pain mechanisms, but its effect on pruritus, a sensory modality that similarly to pain acts as a protective mechanism, is poorly known and controversial. The effects of the slowreleasing (GYY4137) and spontaneous H2S donors (Na2S and Lawesson's reagent, LR)were evaluated in histamine and compound 48/80 (C48/80)-dependent dorsal skin pruritus and inflammation in male BALB/c mice. Animals were intradermally (i.d.)injected with C48/80 (3 µg/site) or histamine (1 µmol/site) alone or co-injected with Na2S, LR or GYY4137 (within the 0.3 -100 nmol range). The involvement of endogenous H2S and KATP channel-dependent mechanism were also evaluated. Pruritus was assessed by the number of scratching bouts, whilst skin inflammation was evaluated by the extravascular accumulation of intravenously injected 125 I-albumin (plasma extravasation) and myeloperoxidase (MPO) activity (neutrophil recruitment). Histamine or C48/80 significantly evoked itching behavior paralleled by plasma extravasation and increased MPO activity. Na2S and LR significantly ameliorated histamine or C48/80-induced pruritus and inflammation, although these effects were less pronounced or absent with GYY4137. Inhibition of endogenous H2S synthesis exacerbated C48/80-induced responses, whereas the blockade of KATP channels by glibenclamide did not. Highperformance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) revealed that Na2S and LR, but not GYY4137, significantly attenuated C48/80-induced histamine release from rat peritoneal mast cell in vitro. We provide first evidences that H2S exerted protective effect against acute pruritus mediated via histaminergic pathways in murine skin, thus making of H2S donors a potential alternative/complementary therapy for treatment of acute pruritus.

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A Counterpart to Pain

Kardon

Ross

2013

Pain Genetics

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Pain is not the only defense mechanism that alerts us to a physical hazard -the other is itch, an unpleasant sensation that is distinct from pain because it provokes the desire to scratch. Although pain and itch feel different, these two sensations share many qualities. Both are aversive sensations that evolved to protect us. Moreover, both can become pathological, developing into chronic debilitating conditions that ruin one's quality of life.Itch, in particular, represents the most common reason that a patient sees a dermatologist. It is estimated that ~10% of the general population and 30% of the elderly suffer from pruritis (the medical term for itch), which negatively affects sleep, mood, and quality of life, thereby presenting an enormous health burden (Weisshaar and Dalgard, 2009;Yosipovitch, 2008). Despite this prevalence, itch has received little attention, and the genetic underpinnings of itch sensitivity are virtually unknown. Here we discuss the limited number of genetic mutations in humans and in mice that have been found to affect itch sensitivity -either heightening or reducing it -and what such mutations tells us about how itch is detected and encoded in the nervous system. Why do we scratch?Scratching in response to a noxious agent is seen across vertebrates, who use this strategy to remove potential threats from the skin's surface, thereby minimizing exposure to harm. Even fish scratch, typically using tail fins or by rubbing against abrasive rocks (Stein, 1983). The highly conserved nature of this scratching response suggests that itch, like pain, confers an important evolutionary advantage. The basics of itchThe key difference between itch and pain is that itch is triggered by noxious stimuli at the very outermost aspect of the skin, whereas pain can be elicited from all cutaneous layers, ranging from superficial to deep, as well as most other regions of the body (Ross, 2011). Thus, the primary sensory neurons that detect pruritic stimuli are postulated to be a subset of dorsal root ganglia (DRG) and trigeminal neurons (perhaps 5%) that selectively innervate the dermis. Most itch fibers are likely to be a subset of unmyelinated, slowly conducting C-fibers, though recent studies suggest that some Aδ fibers may also be involved mediating itch (Ringkamp et al., 2011).What is the identity of these fibers? Remarkably, we do not yet know which sensory fibers mediate itch. Moreover, whether this subset of sensory neurons is specific for itch remains highly controversial. The best evidence that there exists a dedicated subset of peripheral sensory neurons that are selectively tuned to convey itch rather than nociception comes from experiments performing microneurography in humans. Using this technique, it is possible to isolate the activity of individual nerve fibers and identify those that respond to itch-inducing chemicals. Such experiments led to the discovery of C-fibers that are activated by pruritogens and whose activity corresponds to the sensation of itch in humans (Schmelz et al., 1997). Furt...

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Activation of Proteinase-Activated Receptors Induces Itch-Associated Response Through Histamine-Dependent and -Independent Pathways in Mice

Cited by 50 publications

References 14 publications

Involvement of Tryptase and Proteinase-Activated Receptor-2 in Spontaneous Itch-Associated Response in Mice With Atopy-like Dermatitis

Involvement of Tryptase and Proteinase-Activated Receptor-2 in Spontaneous Itch-Associated Response in Mice With Atopy-like Dermatitis

Protective effects of exogenous and endogenous hydrogen sulfide in mast cell-mediated pruritus and cutaneous acute inflammation in mice

A Counterpart to Pain

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