Journal Club 2014.11.24

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Descending Control of Itch Transmission by the Serotonergic System via 5-HT1A-Facilitated GRP-GRPR Signaling

Highlights

  • •Central 5-HT signaling facilitates itch transmission
  • •5-HT1A potentiates GRPR-mediated itch signaling
  • •5-HT1A and GRPR are present in close proximity
  • •Blockade of 5-HT1A function reduces chronic itch

Summary

Central serotonin (5-hydroxytryptophan, 5-HT) modulates somatosensory transduction, but how it achieves sensory modality-specific modulation remains unclear. Here we report that enhancing serotonergic tone via administration of 5-HT potentiates itch sensation, whereas mice lacking 5-HT or serotonergic neurons in the brainstem exhibit markedly reduced scratching behavior. Through pharmacological and behavioral screening, we identified 5-HT1A as a key receptor in facilitating gastrin-releasing peptide (GRP)-dependent scratching behavior. Coactivation of 5-HT1A and GRP receptors (GRPR) greatly potentiates subthreshold, GRP-induced Ca2+ transients, and action potential firing of GRPR+ neurons. Immunostaining, biochemical, and biophysical studies suggest that 5-HT1A and GRPR may function as receptor heteromeric complexes. Furthermore, 5-HT1A blockade significantly attenuates, whereas its activation contributes to, long-lasting itch transmission. Thus, our studies demonstrate that the descending 5-HT system facilitates GRP-GRPR signaling via 5-HT1A to augment itch-specific outputs, and a disruption of crosstalk between 5-HT1A and GRPR may be a useful antipruritic strategy.

Journal Club 2014.11.17

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Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus

supplementary neural peptidase

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus.

Kido-Nakahara M, Buddenkotte J, Kempkes C, Ikoma A, Cevikbas F, Akiyama T, Nunes F, Seeliger S, Hasdemir B, Mess C, Buhl T, Sulk M, Müller FU, Metze D,Bunnett NW, Bhargava A, Carstens E, Furue M, Steinhoff M.

Abstract

In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin-converting enzyme 1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1-containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1-induced activation of ERK1/2, but not p38. In a murine itch model, ET-1-induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1-induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.

journal club 2014-11-10

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The Gardenia jasminoides extract and its constituent, geniposide, elicit anti-allergic effects on atopic dermatitis by inhibiting histamine in vitro and in vivo

Abstract

Ethnopharmacological relevance

Gardenia jasminoides Ellis has been used in traditional medicine for treatment of inflammation, edema, and dermaitis. The aim of this study was to investigate the mechanism by which Gardenia jasminoides extract (GJE) elicits anti-allergic effects in mast cells and in mice with atopic dermatitis (AD).

Materials and methods

We investigated the effects of GJE and its fractions on compound 48/80-induced histamine release from MC/9 cells and Dermatophagoides farinae-exposed NC/Nga mice. The effects of its constituents on histamine release from MC/9 cells were also investigated.

Results

GJE and its ethyl acetate fraction (GJE-EA) inhibited compound 48/80-induced histamine release from MC/9 mast cells. The topical application of GJE or GJE-EA to Dermatophagoides farinae-exposed NC/Nga mice reduced the symptoms of AD, inhibited the infiltration of inflammatory cells, and lowered the serum levels of immunoglobulin E and histamine. Both GJE and GJE-EA reduced the expression of cytokines (interleukin [IL]-4, IL-6, and tumor necrosis factor-alpha) and adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) in ear lesions. In addition, the quantitative analysis of GJE and GJE-EA by high-performance liquid chromatography revealed the presence of crocin and geniposide. Geniposide, but not crocin, inhibited the release of histamine from mast cells, which may contribute to the anti-allergic effect of GJE and GJE-EA.

Conclusions

These results suggest that GJE and GJE-EA can suppress mast cell degranulation-induced histamine release, and geniposide may be potential therapeutic candidates for AD

 

gardenia paper

Journal Club 2014.11.3

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TLR4 enhances histamine-mediated pruritus by potentiating TRPV1 activity (1)
Filename : tlr4-enhances-histamine-mediated-pruritus-by-potentiating-trpv1-activity-1.pdf (2 MB)
Caption :

TLR4 enhances histamine-mediated pruritus by potentiating TRPV1 activity.

Min H, Lee H, Lim H, Jang YH, Chung SJ, Lee CJ, Lee SJ1.

Author information

Abstract

BACKGROUND:

Recent studies have indicated that Toll-like receptor 4 (TLR4), a pathogen-recognition receptor that triggers inflammatory signals in innate immune cells, is also expressed on sensory neurons, implicating its putative role in sensory signal transmission. However, the possible function of sensory neuron TLR4 has not yet been formally addressed. In this regard, we investigated the role of TLR4 in itch signal transmission.

RESULTS:

TLR4 was expressed on a subpopulation of dorsal root ganglia (DRG) sensory neurons that express TRPV1. In TLR4-knockout mice, histamine-induced itch responses were compromised while TLR4 activation by LPS did not directly elicit an itch response. Histamine-induced intracellular calcium signals and inward currents were comparably reduced in TLR4-deficient sensory neurons. Reduced histamine sensitivity in theTLR4-deficient neurons was accompanied by a decrease in TRPV1 activity. Heterologous expression experiments in HEK293T cells indicated thatTLR4 expression enhanced capsaicin-induced intracellular calcium signals and inward currents.

CONCLUSIONS:

Our data show that TLR4 on sensory neurons enhances histamine-induced itch signal transduction by potentiating TRPV1 activity. The results suggest that TLR4 could be a novel target for the treatment of enhanced itch sensation.

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