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Background: Pruritus, or itch, is a prevalent symptom causing profound health burden in many dermatological and non-dermatological disorders. Several itch questionnaires have been created to assess itch. Particularly, Eppendorf Itch Questionnaire (EIQ) is widely accepted since it encompasses various aspects of itch, including intensity, affects, coping behavior, and motivation to scratch., Methods: In a cross-sectional survey, we examined the validity, reliability and clinical utility of Traditional Chinese EIQ., Results: We administered the consensus version to 128 adults (median: 48.5 years, interquartile range [IQR]: 39-63) with active itch for more than 6 weeks at the Outpatient Clinics of three medical centers in Taiwan. Clinical diagnoses included psoriasis (N = 82), xerosis (N = 34), or other dermatitis (N = 12). Cronbach's alpha for each EIQ scale ranged 0.82-0.98, suggesting good to excellent internal consistency and reliability. Three EIQ scales significantly correlated with visual analogue scale (VAS) for itch intensity (P ≤ 0.001 for median test), supporting for its concurrent validity. None of EIQ scale was statistically correlated with Psoriasis Area Severity Index (PASI) scores in psoriasis patients, confirming its discriminant validity. Moreover, patients of different diagnoses had distinct responses to the multi-scale EIQ index, affording it a better clinical test (area-under-the-ROC curve [AUC]: 0.76, 95% CI: 0.63-0.90) than VAS alone (AUC: 0.42, 95%CI: 0.24-0.59) in distinguishing dermatitis/eczema-related itch from psoriasis or xerosis-related itch., Conclusion: We demonstrated the reliability and validity of Chinese EIQ in adult patients with chronic itch at the outpatient setting. The study also revealed the diversified aspects of itch across patients with various dermatoses., Competing Interests: Declaration of Competing Interest The authors declared no conflict of interest., (Copyright © 2020 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Neurologic insults as varied as inflammation, stroke, and fibromyalgia elicit neuropathic pain and itch. Noxious sensation results when aberrantly increased afferent signaling reaches percept-forming cortical neurons and can occur due to increased sensory signaling, decreased inhibitory signaling, or a combination of both processes. To treat these symptoms, detailed knowledge of sensory transmission, from innervated end organ to cortex, is required. Molecular, genetic, and behavioral dissection of itch in animals and patients has improved understanding of the receptors, cells, and circuits involved. In this review, we will discuss neuropathic itch with a focus on the itch-specific circuit.

Itch-specific neurons have been sought for decades. The existence of such neurons has been doubted recently as a result of the observation that itch-mediating neurons also respond to painful stimuli. We genetically labeled and manipulated MrgprA3(+) neurons in the dorsal root ganglion (DRG) and found that they exclusively innervated the epidermis of the skin and responded to multiple pruritogens. Ablation of MrgprA3(+) neurons led to substantial reductions in scratching evoked by multiple pruritogens and occurring spontaneously under chronic itch conditions, whereas pain sensitivity remained intact. Notably, mice in which TRPV1 was exclusively expressed in MrgprA3(+) neurons exhibited itch, but not pain, behavior in response to capsaicin. Although MrgprA3(+) neurons were sensitive to noxious heat, activation of TRPV1 in these neurons by noxious heat did not alter pain behavior. These data suggest that MrgprA3 defines a specific subpopulation of DRG neurons mediating itch. Our study opens new avenues for studying itch and developing anti-pruritic therapies.

Itch has been defined as an unpleasant skin sensation that triggers the urge to scratch. Primary sensory dorsal root ganglia neurons detect itch stimuli through peripheral axons in the skin, playing an important role in generating itch. Itch is broadly categorized as histaminergic (sensitive to antihistamines) or nonhistaminergic. The peptide Ser-Leu-Ile-Gly-Arg-Leu (SLIGRL) is an itch-inducing agent widely used to study histamine-independent itch. Here, we show that Mrgprs (Mas-related G protein-coupled receptors), particularly MrgprC11, rather than PAR2 (protease-activated receptor 2) as previously thought, mediate this type of itch. A shorter peptide, SLIGR, which specifically activates PAR2 but not MrgprC11, induced thermal pain hypersensitivity in mice but not a scratch response. Therefore, although both Mrgpr and PAR2 are SLIGRL-responsive G protein-coupled receptors present in dorsal root ganglia, each plays a specific role in mediating itch and pain.

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., (Copyright 2009 Elsevier Inc. All rights reserved.)