Journal Club 2015.5.22

jid2015183a
Filename : jid2015183a.pdf (3 MB)
Caption :

Mechanisms Underlying the Scratching Behavior Induced by the Activation of Proteinase Activated Receptor-4 (PAR-4) in Mice.

Abstract

A role for proteinase-activated receptor-4 (PAR-4) was recently suggested in itch sensation. Here, we investigated the mechanisms underlying the pruriceptive actions of the selective PAR-4 agonist AYPGKF-NH2 (AYP) in mice. Dorsal intradermal (i.d.) administration of AYP elicited intense scratching behavior in mice, which was prevented by the selective PAR-4 antagonist (pepducin P4pal-10). PAR-4 was found to be co-expressed in 32% of tryptase-positive skin mast cells and AYP caused a 2-fold increase in mast cell degranulation. However, neither the treatment with cromolyn nor the deficiency of mast cells (WBB6F1-KitW/Wv mice) were able to affect AYP-induced itch. PAR-4 was also found on gastrin releasing peptide (GRP)-positive neurons (pruriceptive fibers), and AYP-induced itch was reduced by the selective GRP receptor antagonist RC-3095. In addition, AYP evoked calcium influx in ∼1.5% of cultured DRG neurons also sensitive to TRPV1 (capsaicin) and/or TRPA1 (AITC) agonists. Importantly, AYP-induced itch was reduced by treatment with either the selective TRPV1 (SB366791), TRPA1 (HC-030031) or NK1 (FK888) receptor antagonists. However, genetic loss of TRPV1, but not of TRPA1, diminished AYP-induced calcium influx in DRG neurons and the scratching behavior in mice. These findings provide evidence that PAR-4 activation by AYP causes pruriceptive itch in mice via a TRPV1/TRPA1-dependent mechanism.Journal of Investigative Dermatology accepted article preview online, 08 May 2015. doi:10.1038/jid.2015.183.jid2015183a

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2015-05-15 Journal Club

TriCalm® hydrogel is significantly superior to 2% diphenhydramine and 1% hydrocortisone in reducing the peak intensity, duration, and overall magnitude of cowhage-induced itch

Clin Cosmet Investig Dermatol. 2015 Apr 24;8:223-9. doi: 10.2147/CCID.S78809. eCollection 2015.

Author information

 CCID-78809-tricalm—hydrogel-is-sig

Abstract

BACKGROUND:

Itch is one of the most frequent skin complaints and its treatment is challenging. From a neurophysiological perspective, two distinct peripheral and spinothalamic pathways have been described for itch transmission: a histaminergic pathway and a nonhistaminergic pathway mediated by protease-activated receptors (PAR)2 and 4. The nonhistaminergic itch pathway can be activated exogenously by spicules of cowhage, a tropical plant that releases a cysteine protease named mucunain that binds to and activates PAR2 and PAR4.

PURPOSE:

This study was conducted to assess the antipruritic effect of a novel over-the-counter (OTC) steroid-free topical hydrogel formulation, TriCalm(®), in reducing itch intensity and duration, when itch was induced with cowhage, and compared it with two other commonly used OTC anti-itch drugs.

STUDY PARTICIPANTS AND METHODS:

This double-blinded, vehicle-controlled, randomized, crossover study recorded itch intensity and duration in 48 healthy subjects before and after skin treatment with TriCalm hydrogel, 2% diphenhydramine, 1% hydrocortisone, and hydrogel vehicle, used as a vehicle control.

RESULTS:

TriCalm hydrogel significantly reduced the peak intensity and duration of cowhage-induced itch when compared to the control itch curve, and was significantly superior to the two other OTC antipruritic agents and its own vehicle in antipruritic effect. TriCalm hydrogel was eight times more effective than 1% hydrocortisone and almost six times more effective than 2% diphenhydramine in antipruritic action, as evaluated by the reduction of area under the curve.

CONCLUSION:

TriCalm hydrogel has a robust antipruritic effect against nonhistaminergic pruritus induced via the PAR2 pathway, and therefore it could represent a promising treatment option for itch.

KEYWORDS:

antipruritic treatment; head-to-head comparison; nonhistaminergic pruritus

PMID:
25941445
[PubMed]
PMCID:
PMC4416640

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Journal Club 2015.5.8

Cross-inhibition of NMBR and GRPR signaling maintains normal histaminergic itch transmission.

Abstract

We previously showed that gastrin-releasing peptide receptor (GRPR) in the spinal cord is important for mediating nonhistaminergic itch. Neuromedin B receptor (NMBR), the second member of the mammalian bombesin receptor family, is expressed in a largely nonoverlapping pattern with GRPR in the superficial spinal cord, and its role in itch transmission remains unclear. Here, we report that Nmbr knock-out (KO) mice exhibited normal scratching behavior in response to intradermal injection of pruritogens. However, mice lacking both Nmbr and Grpr (DKO mice) showed significant deficits in histaminergic itch. In contrast, the chloroquine (CQ)-evoked scratching behavior of DKO mice is not further reduced compared with Grpr KO mice. These results suggest that NMBR and GRPR could compensate for the loss of each other to maintain normal histamine-evoked itch, whereas GRPR is exclusively required for CQ-evoked scratching behavior. Interestingly, GRPR activity is enhanced in Nmbr KO mice despite the lack of upregulation of Grpr expression; so is NMBR in Grpr KO mice. We found that NMB acts exclusively through NMBR for itch transmission, whereas GRP can signal through both receptors, albeit to NMBR to a much lesser extent. Although NMBR and NMBR(+) neurons are dispensable for histaminergic itch, GRPR(+) neurons are likely to act downstream of NMBR(+) neurons to integrate NMB-NMBR-encoded histaminergic itch information in normal physiological conditions. Together, we define the respective function of NMBR and GRPR in itch transmission, and reveal an unexpected relationship not only between the two receptors but also between the two populations of interneurons in itch signaling.

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journal club 2015-05-01

Mutual upregulation of endothelin-1 and IL-25 in atopic dermatitis.

Abstract

BACKGROUND:

Endothelin 1 (ET-1) has been reported to evoke histamine-independent pruritus in mammals. However, its association with pruritus or inflammation of atopic dermatitis (AD) has not been clarified. We sought to investigate the role of ET-1 in the skin inflammation of AD.

METHODS:

To examine the role of ET-1 in AD, we investigated the expression of ET-1 and IL-25 in the skin of an AD mouse model and AD patients, and examined the mutual regulatory relationship between ET-1 and IL-25, one of the important cytokines in AD, using the human HaCaT keratinocyte cell line.

RESULTS:

We immunohistochemically confirmed the upregulation of ET-1 and IL-25 expression in the epidermis of both the AD mouse model and AD patients. In vitro, IL-25 upregulated ET-1 mRNA and protein expression in a concentration- and time-dependent fashion in HaCaT cells. This IL-25-induced ET-1 expression was inhibited by ERK1/2 or JNK inhibitor. In a reciprocal manner, ET-1 also induced IL-25 upregulation. The enhancing effect of ET-1 on IL-25 was inhibited by an endothelin A receptor antagonist, ERK1/2 inhibitor or p38 inhibitor, but not by an endothelin B receptor antagonist or JNK inhibitor.

CONCLUSION:

These findings suggest that mutual upregulation of ET-1 and IL-25 takes place in the epidermis in AD, which may be a future target for anti-pruritic agents. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS:

MAPK ; IL-25; Keratinocyte; atopic dermatitis; endothelin-1

 

http://onlinelibrary.wiley.com/doi/10.1111/all.12633/pdf

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Journal Club 2015.4.17

Structure of the TRPA1 ion channel suggests regulatory mechanisms

Candice E. Paulsen1*, Jean-Paul Armache2*, Yuan Gao1,2, Yifan Cheng2 & David Julius1

doi:10.1038/nature14367 nature14367

The TRPA1 ion channel (also known as the wasabi receptor) is a detector of noxious chemical agents encountered in our environment or produced endogenously during tissue injury or drug metabolism. These include a broad class of electrophiles that activate the channel through covalent protein modification. TRPA1 antagonists hold potential for treating neurogenic inflammatory conditions provoked or exacerbated by irritant exposure. Despite compelling reasons to understand TRPA1 function, structural mechanisms underlying channel regulation remain obscure. Here we use single-particle electron cryo- microscopy to determine the structure of full-length human TRPA1 to 4 A ̊ resolution in the presence of pharmacophores, including a potent antagonist. Several unexpected features are revealed, including an extensive coiled-coil assembly domain stabilized by polyphosphate co-factors and a highly integrated nexus that converges on an unpredicted transient receptor potential (TRP)-like allosteric domain. These findings provide new insights into the mechanisms of TRPA1 regulation, and establish a blueprint for structure-based design of analgesic and anti-inflammatory agents.

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Journal Club 2015.4.10

Antipruritic effect of cold stimulation at the Quchi Acupoint (LI11) in Mice

Kao-Sung Tsai123, Yung-Hsiang Chen12, Huey-Yi Chen12, Ein-Yiao Shen12, Yu-Chen Lee12, Jui-Lung Shen45, San-Yuan Wu1, Jaung-Geng Lin12, Yi-Hung Chen1* and Wen-Chi Chen12*

Abstract

Background

Acupuncture and moxibustion are used to treat pruritus and atopic dermatitis. However, whether cold stimulation (defined as that the temperature conducted under skin temperature) of acupoints affects itching in experimental murine models remains unclear.

Methods

The present study was designed to determine the therapeutic effects of different thermal stimulations at the Quchi acupoint (LI11) in a murine model in which scratching behaviour was elicited by subcutaneous injection with a pruritogenic agent (compound 48/80). Male ICR mice were divided into several groups as follows: control (saline), those receiving compound 48/80 and compound 48/80 with various thermal stimulations (5°C–45°C) at LI11 (n = 6 per group). The scratch response of each animal to these stimulations was recorded for 30 min. The antipruritic effect of the acupoint was further evaluated in LI11 and sham (non-acupoint) groups (n = 6 per group).

Results

Treatment with lower temperature (20°C) at the LI11 acupoint significantly attenuated compound 48/80-induced scratching; however, this antipruritic effect was not observed with stimulation at the sham point. The expression of c-fos in the neuron of the cervical spine induced by compound 48/80 was suppressed by cold stimulation at LI11. The antipruritic effect of cold stimulation was blocked by ruthium red (RR), a non-selective transient receptor potential (TRP) channel blocker, suggesting that TRP channels may play an important role in the antipruritic effect of cold stimulation at LI11 in mice.

Conclusions

This study demonstrated that cold stimulation at LI11 attenuated compound 48/80-induced scratching behaviour in mice, possibly by a TRP-related pathway.

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Journal Club 2015.4.3

4200
Filename : 4200.pdf (619 KB)
Caption :

Gender Differences in Itch and Pain-related Sensations Provoked by Histamine, Cowhage and Capsaicin

Abstract:

Cowhage, capsaicin and histamine, all applied via spicules, were used to induce itch and pain-related sensations in 15 male and 15 female subjects. Sensory qualities were assessed by questionnaire; intensities and time courses of the “itching” and “burning” sensation were measured alternately, but continuously on a VAS. In addition, axon reflexes were assessed. Only histamine and capsaicin produced a clear axon reflex flare (histamine > capsaicin, male = female). The 3 types of spicules caused mixed burning and itching sensations with different time courses. In the beginning burning prevailed, in the following minutes histamine induced mostly itching, capsaicin predominantly burning, cowhage both sensory components equally. Female subjects experienced more pain-related sensations (questionnaire), and their ratings leaned more toward burning than those of males. These findings indicate that the mixed itching and burning sensations are differentially processed by both genders. No indications were found for gender specific differential processing in the primary afferents as reflected by nearly identical flare responses.

Authors:

Elisabeth M. Hartmann, Herman O. Handwerker, Clemens Forster

Journal Club 2015.4.3 Read More »

journal clb 27-3-2015

Gamisasangja-tang suppresses pruritus and atopic skin inflammation in the NC/Nga murine model of atopic dermatitis

Abstract

Ethnopharmacological relevance

Gamisasangja-tang (GST) is a traditional herbal formula prescribed for patients with intractable pruritus in association with various inflammatory skin diseases. To evaluate the effects of GST on pruritic skin inflammation and investigate its cellular and molecular mechanisms.

Materials and methods

We orally administered GST to NC/Nga (NC) mice, an animal model of atopic dermatitis. Scratching frequency and the dermatitis index were evaluated, and histological examination was performed using hematoxylin and eosin and toluidine blue staining. The levels of interleukin (IL)-31 and T-helper cell type 2 (TH2) cytokines were determined in both the dorsal skin and cultured splenocytes by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The serum levels of chemokines and immunoglobulin E (IgE) were determined by ELISA. Changes in the inflammatory cell population were analyzed by a hemocytometer.

Results

GST significantly lowered scratching frequency and inhibited increases in dermatitis index, thickness of epidermis/dermis and infiltration of chemokine (C-C motif) receptor 3 (CCR3)+ and cluster of differentiation (CD)117+/FcεRIα (Fc fragment of IgE, high affinity I, receptor for; alpha polypeptide)+ cells in atopic skin. Both IL-31 mRNA expression and production were significantly reduced by GST, which was accomrease in the levels of IL-4, IL-5, and IL-13. Further, GST treatment suppressed the secretion of eotaxin, TARC (thymus and activation-regulated chemokine), IgE, and increases in the number of basophils and eosinophils in the blood.

Conclusion

GST may have potential as an effective treatment for pruritic skin disease such as atopic dermatitis

gamisasangja tang

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Journal club 2015.3.20

Nalfurafine suppresses pruritogen– and touch-evoked scratching behavior in models of acute and chronic itchin mice.

Abstract

The kappa-opioid agonist, nalfurafine, has been approved in Japan for treatment of itch in patients with chronic kidney disease. We presently investigated if systemic administration of nalfurafine inhibited ongoing or touch-evoked scratching behavior (alloknesis) following acuteintradermal injection of histamine or the non-histaminergic itch mediator, chloroquine, in mice. We also investigated if nalfurafine suppressed spontaneous or touch-evoked scratching in an experimental model of chronic dry skin itch. Nalfurafine reduced scratching evoked by histamine and chloroquine. Following acute histamine, but not chloroquine, low-threshold mechanical stimuli reliably elicited directed hindlimb scratchingbehavior, which was significantly attenuated by nalfurafine. In mice with experimental dry skin, nalfurafine abolished spontaneous scratching but had no effect on alloknesis. Nalfurafine thus appears to be a promising treatment for acute itch as well as ongoing itch of dry skin.

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