A histamine-independent itch path- way is required for allergic ocular itch

A histamine-independent itch pathway is required for allergic ocular itch

Cheng-Chiu Huang, PhDa, Yu Shin Kim, PhDb, William P. Olson, BSc, Fengxian Li, MDa, d, Changxiong Guo, BAa, Wenqin Luo, MD, PhDc, Andrew J.W. Huang, MD, MPHe, Qin Liu, PhDa, e,

From athe Department of Anesthesiology and the Center for the Study of Itch, Washing- ton University School of Medicine, St Louis, Mo; bthe Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Md; cthe Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pa; dthe Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, China; and ethe Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, Mo.

Itch is the cardinal symptom of allergic conjunctivitis and afflicts 15% to 20% of the population worldwide. Histamine produced by conjunctival mast cells has been implicated as the principal itch mediator that activates histamine receptors on primary sensory fibers to induce allergic ocular itch.1 However, antihistamines cannot completely relieve ocular itch in many cases, suggesting the involvement of a histamine-independent itch pathway. Herein, we sought to identify the histamine- independent neural pathway involved in allergic conjunctivitis and to develop new therapeutic strategies for allergic ocular itch.

Faciliation of TRPV4-TRPV1 itch Science Signaling 2016.full

Authors: Seungil Kim, Devin M. Barry, Xian-Yu Liu, Shijin Yi, Admire Munanairi, Qing-Tao Meng, Wei Cheng, Ping Mo, Li Wan, Shen-Bin Liu, Kasun Ratnayake, Zhong-Qiu Zhao, Narasimhan, GautamJie Zheng, W. K. Ajith Karunarathne, Zhou-Feng Chen

The transient receptor potential channels (TRPs) respond to chemical irritants and temperature. TRPV1 responds to the itch-inducing endogenous signal histamine, and TRPA1 responds to the itch-inducing chemical chloroquine. We showed that, in sensory neurons, TRPV4 is important for both chloroquine and histamine-induced itch and that TRPV1 has a role in chloroquine-induced itch. Chloroquine-induced scratching was reduced in mice in which TRPV1 was knocked down or pharmacologically inhibited. Both TRPV4 and TRPV1 were present in some sensory neurons. Pharmacological blockade of either TRPV4 or TRPV1 significantly attenuated the Ca2+ response of sensory neurons exposed to histamine or chloroquine.
Knockout of Trpv1 impaired Ca2+ responses and reduced scratching behavior evoked by a TRPV4 agonist, whereas knockout of Trpv4 did not alter TRPV1-mediated capsaicin responses. Electrophysiological analysis of human embryonic kidney (HEK) 293 cells coexpressing TRPV4 and TRPV1 revealed that the presence of both channels enhanced the activation kinetics of TRPV4 but not of TRPV1. Biochemical and biophysical studies suggested a close proximity between TRPV4 and TRPV1 in dorsal root ganglion neurons and in cultured cells. Thus, our studies identified TRPV4 as a channel that contributes to both histamine- and chloroquine-induced itch and indicated that the function of TRPV4 in itch signaling involves TRPV1-mediated facilitation. TRP facilitation through the formation of heteromeric complexes could be a prevalent mechanism by which the vast array of somatosensory information is encoded in sensory neurons.

Title: Stimulation of the histamine 4 receptor upregulates thymic stromal lymphopoietin (TSLP) in human and murine keratinocytes
Author: Katrin Schaper Dr. Kristine Rossbach Brigitta K¨other Holger Stark Manfred Kietzmann Thomas Werfel Ralf Gutzmer

Abstract
The cytokine thymic stromal lymphopoietin (TSLP) is involved in the development and the
progression of allergic diseases. It is mainly released by epithelial cells at barriers such as skin
and gut in response to danger signals. Overexpression of TSLP in keratinocytes (KC) can
Keratinocyte can provoke the development of a type 2 inflammatory response. Additionally, TSLP directly acts on sensory neurons and thereby triggers itch. Since histamine is also increased in lesions of inflammatory skin diseases, the aim of this study was to investigate possible effects of histamine as well as different histamine receptor subtype agonists and antagonists on TSLP production in KC. We therefore stimulated human KC with histamine in the presence or absence of the known TSLP-inductor poly I:C and measured TSLP production at protein as well as mRNA level. Histamine alone did not induce TSLP production in human KC, but preincubation with histamine prior to challenge with poly I:C resulted in a significant increase of TSLP production compared to stimulation with poly I:C alone. Experiments with different histamine receptor agonists (H1R: 2-pyridylethylamine ; H2R: amthamine; H2R/H4R: 4-
methylhistamine (4MH)) revealed a dominant role for the H4R receptor, as 4-MH in
combination with poly I:C displayed a significant increase of TSLP secretion, while the other
agonists did not show any effect. The increase in TSLP production by 4MH was blocked with
the H4R antagonist JNJ7777120. This effect was reproducible also in the murine KC cell line
MSC.
Taken together, our study indicates a new role for the H4 receptor in the regulation of TSLP
in keratinocytes. Therefore, blocking of the H4R receptor in allergic diseases might be
promising to alleviate inflammation and pruritus via TSLP.
Keywords: TSLP, histamine, histamine 4 receptor, keratinocytes

Stimulation of the histamine 4 receptor upregulates thymic stromal lymphopoietin (TSLP) in human and murine keratinocytes

Enhanced itch elicited by capsaicin in a chronic itch model

Enhanced itch elicited by capsaicin in a chronic itch model

Guang Yu, PhD1,2, Niuniu Yang, MD1, Fengxian Li, MD2,3, Meijuan Chen, PhD1, Changxiong J Guo, BS2, Changming Wang, PhD1, Danyou Hu, BS1, Yan Yang, BS1, Chan Zhu, BS1,
Zhongli Wang, PhD1, Hao Shi, MD1, Tana Gegen, MD1, Ming Tang, MS1, Qian He, MS1, Qin Liu, PhD2 and Zongxiang Tang, PhD1

Abstract
Chronic itch (pruritus) is an important clinical problem. However, the underlying molecular basis has yet to be understood. The Transient Receptor Potential Vanilloid 1 channel is a heat-sensitive cation channel expressed in primary sensory neurons and involved in both thermosensation and pain, but its role in chronic itch remains elusive. Here, we for the first time revealed an increased innervation density of Transient Receptor Potential Vanilloid 1-expressing sensory fibers in the skin afflicted with chronic itch. Further analysis indicated that this phenomenon is due to an expansion of Transient Receptor Potential Vanilloid 1-expressing sensory neurons under chronic itch conditions. As a functional correlates of this neuronal expansion, we observed an enhanced neuronal responsiveness to capsaicin under the dry skin conditions. Importantly, the neuronal hypersensitivity to capsaicin results in itch, rather than pain sensation, suggesting that the up-regulated Transient Receptor Potential Vanilloid 1 underlies the pain-to-itch switch under chronic itchy conditions. The study shows that there are different mechanisms of chronic pain and itching, and Transient Receptor Potential Vanilloid 1 plays an important role in chronic itch.

Keywords
Chronic itch, pain, Transient Receptor Potential Vanilloid 1, calcium imaging Date received: 5 January 2016; revised: 20 March 2016; accepted: 20 March 2016

Proteinase-activated receptor 1 contributed to up-regulation of enkephalin in keratinocytes of patients with obstructive jaundice.

Tao KM , Tao Y , Chen CY , Yang LQ , Lu ZJ , Sun YM , Huang SD , Yu WF

ABSTRACT
Background: Skin synthesis of endogenous opioids such as enkephalin is considered to be increased in cholestatic rodents, which may induce antinociception in cholestatic liver disease. No studies have reported yet the expression of skin enkephalin in patients with cholestasis.

 
Methods: Electrical pain threshold, postoperative morphine consumption, and skin enkephalin expression were measured in patients with jaundice (n = 18) and control patients (n = 16). Male Sprague–Dawley rats (n = 52) and human keratinocyte cell line HaCaT were used in vivo and in vitro studies, respectively. Nociceptive thresholds and plasma and skin levels of methionine-enkephalin were compared in protease-activated receptors-1–antagonized and control bile duct–ligated rats. In in vitro study, the effect on thrombin-induced enkephalin expression was examined and the role of extracellular regulated protein kinases 1/2 and p38 was investigated.

 
Results: The authors found that: (1) the electrical pain threshold (mean ± SD) was 1.1 ± 0.1 mA in control patients, whereas it was significantly increased in patients with jaundice (1.7 ± 0.3 mA); 48-h postoperative morphine consumption was approximately 50% higher in the control group than that in the group with jaundice; (2) Skin keratinocytes enkephalin expression
was increased in the patients with jaundice; (3) Protease-activated receptors-1 antagonist 1 μg·kg−1·day−1 treatment to the bile duct–ligated rats significantly reduced plasma levels of methionine-enkephalin, nociceptive thresholds, and keratinocytes enkephalin expression; and (4) protease-activated receptors-1 activation induced enkephalin expression through phosphorylation of extracellular regulated protein kinases 1/2 and p38 in keratinocytes.

 
Conclusion: Protease-activated receptors-1 activation in peripheral keratinocytes may play an important role in the local synthesis of enkephalin during cholestasis.

Proteinasse-acticated receptor 1 contributed to up-regulation of enkephalin in keratinocytes of patients with jaundice

Dioscin protects against ANIT-induced cholestasis via regulating Oatps, Mrp2 and Bsep expression in rats.

Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity.

Abdullah H¹, Heaney LG, Cosby SL, McGarvey LP.

Abstract

Rhinovirus upregulates TRP

TLR signaling adaptor protein MyD88 in primary sensory neurons contributes to persistent inflammatory and neuropathic pain and neuroinflammation.

Increased ZAP70 Is Involved in Dry Skin Pruritus in Aged Mice

¹Institute of Neuroscience, Department of Human Anatomy, Chongqing Medical University, Chongqing 400016, China
²Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

Anti-pruritic effect of baicalin and its metabolites, baicalein and oroxylin A, in mice

Anti-pruritic effect of baicalin and its metabolites, baicalein and oroxylin A, in mice

Hien-trung TRINH1, Eun-ha JOH1, Ho-young KWAK2, Nam-in BAEK2, Dong-hyun KIM1, *
1Department of Pharmaceutical Science and Department of Life and Pharmaceutical Sciences, Kyung Hee University, 1, Hoegi, Dongdaemun-ku, Seoul 130–701, Korea; 2Graduate School of Biotechnology and PMRC, Kyung Hee University, 1, Seochunri, Suwon, Kyunggi-Do 449–701, Korea
Aim: To explore whether intestinal micro ora plays a role in anti-pruritic activity of baicalin, a main constituent of the rhizome of Scutellaria baicalensis (SB).
Methods: Baicalin was anaerobically incubated with human fecal micro ora, and its metabolites, baicalein and oroxylin A, were isolated. The inhibitory effect of baicalin and its metabolites was accessed in histamine- or compound 48/80-induced scratching behavior in mice.
Results: Baicalin was metabolized to baicalein and oroxylin A, with metabolic activities of 40.2±26.2 and 1.2±1.1 nmol·h-1·mg-1 wet weight of human fecal micro ora, respectively. Baicalin (20, 50 mg/kg) showed more potent inhibitory effect on histamine-induced scratching behavior when orally administered than intraperitoneally. In contrast, baicalein and oroxylin A had more potent inhibitory effect when the intraperitoneally administered. The anti-scratching behavior activity of oral baicalin and its metabolites was in proportion to their inhibition on histamine-induced increase of vascular permeability with oroxylin A more potent than baicalein and baicalin. In Magnus test using guinea pig ileum, oroxylin A is more potent than baicalein and baicalin in inhibition of histamine-induced contraction. The anti-scratching behavioral effect of oral baicalin was signi cantly reduced when oral antibiotics were simultaneously administered, whereas the effect of baicalein and oroxylin A were not affected.
Conclusion: Oral baicalin may be metabolized by intestinal micro ora into baicalein and oroxylin A, which ameliorate pruritic reactions through anti-histamine action.
Keywords: Scutellaria baicalensis; baicalin; baicalein; oroxylin A; scratching behavior; metabolism; histamine Acta Pharmacologica Sinica (2010) 31: 718–724; doi: 10.1038/aps.2010.42; published online 10 May 2010