Fluoxetin ameliorates Atopic Dermatitis like skin lesions in BALB.c mice through reducing psychological stress and Inflammatory response

Inhibition of TRPV1 channels by a naturally occurring omega-9 fatty acid reduces pain and itch

Inhibition of TRPV1 channels by a naturally occurring omega-9 fatty acid reduces pain and itch

Sara L. Morales-La ́zaro1, Itzel Llorente1, Fe ́lix Sierra-Ram ́ırez1, Ana E. Lo ́pez-Romero1, Miguel Ort ́ız-Renter ́ıa1, Barbara Serrano-Flores1, Sidney A. Simon2, Leo ́n D. Islas3 & Tamara Rosenbaum1

The transient receptor potential vanilloid 1 (TRPV1) ion channel is mainly found in primary nociceptive afferents whose activity has been linked to pathophysiological conditions including pain, itch and inflammation. Consequently, it is important to identify naturally occurring antagonists of this channel. Here we show that a naturally occurring mono- unsaturated fatty acid, oleic acid, inhibits TRPV1 activity, and also pain and itch responses in mice by interacting with the vanilloid (capsaicin)-binding pocket and promoting the stabilization of a closed state conformation. Moreover, we report an itch-inducing molecule, cyclic phosphatidic acid, that activates TRPV1 and whose pruritic activity, as well as that of histamine, occurs through the activation of this ion channel. These findings provide insights into the molecular basis of oleic acid inhibition of TRPV1 and also into a way of reducing the pathophysiological effects resulting from its activation.

1 Instituto de Fisiolog ́ıa Celular, Universidad Nacional Auto ́noma de Me ́xico, Circuito exterior s/n, Coyoacan 04510, Mexico. 2 Department of Neurobiology, Duke University, 327C Bryan Research Building, Durham, North Carolina 27710, USA. 3 Departamento de Fisiolog ́ıa, Facultad de Medicina, Universidad Nacional Auto ́noma de Me ́xico, Circuito escolar s/n, Coyoacan 04510, Mexico. Correspondence and requests for materials should be addressed to T.R. (email: trosenba@ifc.unam.mx).

Ethanol Extract of Sanguisorbae Radix Inhibits Mast Cell Degranulation and Suppresses 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis-Like Skin Lesions.

Involvement of TRPV1 and TDAG8 in pruriception associated with noxious acidosis.

Lin SH¹, Steinhoff M², Ikoma A³, Chang YC⁴, Cheng YR⁵, Chandra Kopparaju R⁶, Ishii S⁷, Sun WH⁴, Chen CC⁸.

involvement of trpv1 and tdag8 in pruriception associated with noxious acidosis

Itch and pain are closely related but distinct sensations. Intradermal injection of acid generates pain in both rodents and humans; however, few studies have addressed the intriguing question of whether proton can evoke itch like other algogens at the basis of spatial contrast activation of single nociceptors. Here, we report that (1) citric acid (0.2 M) pH-dependently induced a scratching response in mice when applied intradermally to nape or cheek skin; (2) acidified buffer elevated intracellular calcium levels in dorsal root ganglion (DRG) pruriceptors; (3) injection of intradermal citric acid (pH 3.0) into the nape induced a pruritogen-like but not algogen-like c-Fos immunoreactivity pattern in the cervical spinal cord. Using pharmacological and genetic approaches, we identified potential acid-sensing channels/receptors involved in acidic citrate-evoked itch. Results indicate that TRPV1 but neither ASIC3 nor TRPA1 are involved in the acidic citrate-induced scratching response. Furthermore, one of the proton-sensing G-protein-coupled receptors, TDAG8, was highly (∼71%) expressed in Nppb⁺ DRG pruriceptors. Acidic citrate but not α-methyl-5-HT, chloroquine, compound 48/80 or bile acid-induced itch was markedly decreased in TDAG8^-/- mice. In a heterologous expression system, TDAG8 potentiated the acid-induced calcium response by regulating TRPV1. Thus, proton could evoke pruriception by acting on TDAG8 to regulate TRPV1 activation with its mechanism of future therapeutic relevance.

The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4.

Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice.

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