Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.

The cellular and molecular mechanisms mediating histamine-independent itch in primary sensory neurons are largely unknown. Itch induced by chloroquine (CQ) is a common side effect of this widely used antimalarial drug. Here, we show that Mrgprs, a family of G protein-coupled receptors expressed exclusively in peripheral sensory neurons, function as itch receptors. Mice lacking a cluster of Mrgpr genes display significant deficits in itch induced by CQ but not histamine. CQ directly excites sensory neurons in an Mrgpr-dependent manner. CQ specifically activates mouse MrgprA3 and human MrgprX1. Loss- and gain-of-function studies demonstrate that MrgprA3 is required for CQ responsiveness in mice. Furthermore, MrgprA3-expressing neurons respond to histamine and coexpress gastrin-releasing peptide, a peptide involved in itch sensation, and MrgprC11. Activation of these neurons with the MrgprC11-specific agonist BAM8-22 induces itch in wild-type but not mutant mice. Therefore, Mrgprs may provide molecular access to itch-selective neurons and constitute novel targets for itch therapeutics.

Liu Q ，Tang Z ，Surdenikova L ，Kim S ，Patel KN ，Kim A ，Ru F ，Guan Y ，Weng HJ ，Geng Y ，Undem BJ ，Kollarik M ，Chen ZF ，Anderson DJ ，Dong X ... -  《-》

TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch.

Wilson SR ，Gerhold KA ，Bifolck-Fisher A ，Liu Q ，Patel KN ，Dong X ，Bautista DM ... -  《-》

Itching, chloroquine, and malaria: a review of recent molecular and neuroscience advances and their contribution to mechanistic understanding and therapeutics of chronic non-histaminergic pruritus.

Chloroquine (CQ) is an antimalarial drug that elicits severe pruritus in black Africans with malaria fever. This acute itching (2-7 days duration) exhibits age dependency and a racial and genetic predilection. CQ itch is non-histaminergic, which makes it both a good model and a tool to probe the mechanisms of chronic itch. This review focuses on recently discovered mechanisms, neuroscience, mediators, and receptors that are implicated in molecular studies of CQ pruritus. CQ pruritus mechanisms are also compared to that of itching following other systemic diseases, such as chronic kidney disease, chronic liver disease, skin disorders, and burns. There are striking similarities between CQ itching pathways and other chronic itch secondary to systemic disease with or without skin lesions, which have not been previously highlighted. Prominent among these are the shared roles of skin, neural and spinal μ opiate receptors, kappa opiate receptor, nitric oxide, serotonin via 5HT1B/D receptors, cytokines, especially interleukins, and tumor necrosis factor. There is elaborate "cross talk" among the diverse mediators and receptors involved in CQ-induced pruritus. CQ also binds to the mas-related G protein coupled receptors MrgprA3/MrgprX1 present in a small proportion (4-5%) of dorsal root ganglion neurons and skin. The mrgprA3 CQ receptors are coupled to PLC-β3 and a chloride channel to initiate skin itch action potentials in C nerve fibers. Mrgpra3/X1 couples to TRPA1 for calcium influx into neuronal cells at noncutaneous sites. Central CQ itch occurs via gastrin-related peptide (GRP) and its receptor (GRPR) in the dorsal spinothalamic tracts, as well as glutamic mediated GRP projection to parabrachial nucleus. The possibility of chronic itch therapy based on personalized medicine, genetics, and transcriptomics or the use of itch "polypill/polycream" are discussed.

Ajayi AAL 《-》

mMrgprA3/mMrgprC11/hMrgprX1: Potential therapeutic targets for allergic contact dermatitis-induced pruritus in mice and humans.

Although the Mas-related G-protein-coupled receptors (Mrgprs) play essential roles in itch detection, their contribution to allergic contact dermatitis (ACD)-associated itch remains unclear. To investigate whether Mrgprs are involved in ACD and whether Mrgprs can be identified as potential therapeutic targets. Mrgpr-clusterΔ-/- mice and human MrgprX1 (hMrgprX1) transgenic mice were used to evaluate the function of Mrgprs in oxazolone-induced ACD. Utilizing an ACD model, we found that Mrgpr-clusterΔ-/- mice display significantly reduced pruritus. Among 12 Mrgprs deleted in Mrgpr-clusterΔ-/- mice, the expression of MrgprC11 and MrgprA3 was significantly increased in the ACD model, which also innervated the skin and spinal cord at higher-than-normal densities. The proportions of dorsal root ganglia neurons responding to bovine adrenal medulla peptide 8-22 and chloroquine were also remarkably increased in the ACD model, resulting in enhanced itch behaviour. To study the function of human Mrgprs in ACD-induced itch, we used hMrgprX1 transgenic mice, which rescued the severe itch defect of Mrgpr-clusterΔ-/- mice in the ACD model. Remarkably, pharmacological blockade of hMrgprX1 significantly attenuates ACD itch in hMrgprX1 transgenic mouse. Our study provides the first evidence that Mrgprs are involved in ACD-induced chronic itch, which provides new avenues for itch management in ACD.

Li F ，Wang C ，Hu D ，Zhang X ，Shen R ，Zhou Y ，Yang Y ，Zhu C ，Tang Z ，Yu G ... -  《-》

Protein kinase Cδ mediates histamine-evoked itch and responses in pruriceptors.

Valtcheva MV ，Davidson S ，Zhao C ，Leitges M ，Gereau RW 4th ... -  《Molecular Pain》