Journal Club 19.03.22.

Facilitation of MrgprD by TRP-A1 promotes neuropathic pain

Changming Wang,*,†,‡,§ Leying Gu,*,†,‡,§ Yonglan Ruan,*,†,‡,§ Xiao Geng,*,†,‡,§ Miao Xu,{ Niuniu Yang,*,k Lei Yu,*,† Yucui Jiang,*,† Chan Zhu,*,†,‡,§ Yan Yang,*,†,‡,§
Yuan Zhou,*,†,‡,§ Xiaowei Guan,*,†,‡,§ Wenqin Luo,# Qin Liu,**,††,‡‡ Xinzhong Dong,§§,{{ Guang Yu,*,†,‡,§,1 Lei Lan,{,2 and Zongxiang Tang*,†,‡,§
*School of Medicine and Life Sciences, †Key Laboratory of Chinese Medicine for Prevention and Treatment of Neurological Diseases, ‡State Key Laboratory Cultivation Base for Traditional Chinese Medicine Quality and Efficacy, and §Key Laboratory of Drug Target and Drug for Degenerative Disease of Jiangsu Province, Nanjing University of Chinese Medicine, Nanjing, China; {Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China; kDepartment of Traditional Chinese and Western Medicine, Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, China; #Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; **Department of Anesthesiology, ††Center for the Study of Itch, and ‡‡Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA; and §§The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, and {{Howard Hughes Medical Institute, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
ABSTRACT: Neuropathic pain remains a therapeutic challenge because of its complicated mechanisms. Mas-related GPCR D (MrgprD) is specifically expressed in small-diameter, nociceptive neurons of dorsal root ganglia (DRGs) and is implicated in pain modulation. However, the underlying mechanism of MrgprD involved in neuropathic pain remains elusive. In this study, we used behavioral experiments and physiologic examination methods to investigate the role of MrgprD in chronic constriction injury (CCI)–induced neuropathic pain. We found that MrgprD is necessary for the initiation of mechanical hypersensitivity and cold allodynia, but not for heat allodynia. Moreover, we demonstrated that transient receptor potential cation channel (TRP)-A1 was the ion channel down- stream of MrgprD, and the b-alanine–induced calcium signal was attributed mostly to TRP-A1 function. We further showed that PKA serves as a downstream mediator of b-alanine–activated MrgprD signaling to activate TRP-A1 in DRG neurons and in human embryonic kidney 293 cells, to coexpress MrgprD and TRP-A1 plasmids. Finally, we found that the b-alanine–induced pain behavior was increased, whereas the itching behavior was unchanged in CCI models compared with sham-injured animals. Knockout of TRPA1 also attenuated the b-alanine–induced pain behavior in CCI models. In conclusion, MrgprD is essential in cold allodynia in CCI-induced neuropathic pain through the PKA–TRP-A1 pathway. TRP-A1 facilitates MrgprD to development of neuropathic pain. Our findings reveal a novel mechanism of neuropathic pain formation and highlight MrgprD as a promising drug target for the treatment of neuropathic pain.—Wang, C., Gu, L., Ruan, Y., Geng, X., Xu, M., Yang, N., Yu, L., Jiang, Y., Zhu, C., Yang, Y., Zhou, Y., Guan, X., Luo, W., Liu, Q., Dong, X., Yu, G., Lan, L., Tang, Z. Facilitation of MrgprD by TRP-A1 promotes neuropathic pain. FASEB J. 33, 1360–1373 (2019). www.fasebj.org
KEY WORDS: MrgprA1 • dorsal root ganglia (DRG) • protein kinase A (PKA)

2019.03.15

By Babina Sanjel

Identification of a bilirubin receptor that may mediate a component of cholestatic itch.

Meixiong J^#¹, Vasavda C^#¹, Green D¹, Zheng Q¹, Qi L¹, Kwatra SG², Hamilton JP³, Snyder SH^1,^4,⁵,

Dong X^1,^2,^6,⁷.

Author information

Abstract

Various pathologic conditions result in jaundice, a yellowing of the skin due to a buildup of bilirubin. Patients with jaundice commonly report experiencing an intense non-histaminergic itch. Despite this association, the pruritogenic capacity of bilirubin itself has not been described, and no bilirubin receptor has been identified. Here, we demonstrate that pathophysiologic levels of bilirubin excite peripheral itch sensory neurons and elicit pruritus through MRGPRs, a family of G-protein coupled receptors expressed in primary sensory neurons. Bilirubin binds and activates two MRGPRs, mouse MRGPRA1 and human MRGPRX4. In two mouse models of pathologic hyperbilirubinemia, we show that genetic deletion of either Mrgpra1 or Blvra, the gene that encodes the bilirubin-producing enzyme biliverdin reductase, attenuates itch. Similarly, plasma isolated from hyperbilirubinemic patients evoked itch in wild-type animals but not Mrgpra1^-/- animals. Removing bilirubin decreased the pruritogenic capacity of patient plasma. Based on these data, targeting MRGPRs is a promising strategy for alleviating jaundice-associated itch.

KEYWORDS:

Mrgpr; bilirubin; cholestasis; itch; mouse; neuroscience; sensory neuron

Identification of a bilirubin receptor that may mediate a component of cholestatic itch

2019.03.08 journal club

By qhsl93

12264_2017_Article_124

TNF-α/TNFR1 Signaling is Required for the Full Expression of Acute and Chronic Itch in Mice via Peripheral and Central Mechanisms.

Miao X¹, Huang Y², Liu TT², Guo R², Wang B², Wang XL³, Chen LH⁴, Zhou Y², Ji RR^5,⁶, Liu T^7,⁸.

Author information

Abstract

Increasing evidence suggests that cytokines and chemokines play crucial roles in chronic itch. In the present study, we evaluated the roles of tumor necrosis factor-alpha (TNF-α) and its receptors TNF receptor subtype-1 (TNFR1) and TNFR2 in acute and chronic itch in mice. Compared to wild-type (WT) mice, TNFR1-knockout (TNFR1-KO) and TNFR1/R2 double-KO (DKO), but not TNFR2-KO mice, exhibited reduced acute itch induced by compound 48/80 and chloroquine (CQ). Application of the TNF-synthesis inhibitor thalidomide and the TNF-α antagonist etanercept dose-dependently suppressed acute itch. Intradermal injection of TNF-α was not sufficient to evoke scratching, but potentiated itch induced by compound 48/80, but not CQ. In addition, compound 48/80 induced TNF-α mRNA expression in the skin, while CQ induced its expression in the dorsal root ganglia (DRG) and spinal cord. Furthermore, chronic itch induced by dry skin was reduced by administration of thalidomide and etanercept and in TNFR1/R2 DKO mice. Dry skin induced TNF-α expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-α/TNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be beneficial for chronic itch treatment.