title: Enhanced nonpeptidergic intraepidermal fiber density and an expanded subset of chloroquine-responsive trigeminal neurons in a mouse model of dry skin itch.
abstract: Chronic pruritic conditions are often associated with dry skin and loss of epidermal barrier integrity. In this study, repeated application of acetone and ether followed by water (AEW) to the cheek skin of mice produced persistent scratching behavior with no increase in pain-related forelimb wiping, indicating the generation of itch without pain. Cheek skin immunohistochemistry showed a 64.5% increase in total epidermal innervation in AEW-treated mice compared to water-treated controls. This increase was independent of scratching, because mice prevented from scratching by Elizabethan collars showed similar hyperinnervation. To determine the effects of dry skin treatment on specific subsets of peripheral fibers, we examined Ret-positive, calcitonin gene-related peptide (CGRP)-positive, and glial cell line-derived neurotrophic factor family receptor α3 (GFRα3)-positive intraepidermal fiber density. AEW treatment increased Ret-positive fibers but not CGRP-positive or GFRα3-positive fibers, suggesting that a specific subset of nonpeptidergic fibers could contribute to dry skin itch. To test whether trigeminal ganglion neurons innervating the cheek exhibited altered excitability after AEW treatment, primary cultures of retrogradely labeled neurons were examined using whole-cell patch clamp electrophysiology. AEW treatment produced no differences in measures of excitability compared to water-treated controls. In contrast, a significantly higher proportion of trigeminal ganglion neurons was responsive to the nonhistaminergic pruritogen chloroquine after AEW treatment. We conclude that nonpeptidergic, Ret-positive fibers and chloroquine-sensitive neurons may contribute to dry skin pruritus.
  
  
  CONCLUSIONS
  This study examines the underlying neurobiological mechanisms of persistent dry skin itch. Our results indicate that nonpeptidergic epidermal hyperinnervation and nonhistaminergic pruritic receptors are potential targets for chronic pruritus.
authors: Washington University Pain Center and Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri; Medical Scientist Training Program, Washington University in St. Louis, St. Louis, Missouri.
authors: Manouela V
authors: MV
authors: Valtcheva
authors: Washington University Pain Center and Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri.
authors: Vijay K
authors: VK
authors: Samineni
authors: Washington University Pain Center and Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri.
authors: Judith P
authors: JP
authors: Golden
authors: Washington University Pain Center and Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri.
authors: Robert W
authors: RW
authors: Gereau
authors: Washington University Pain Center and Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri. Electronic address: sdavidson@wustl.edu.
authors: Steve
authors: S
authors: Davidson
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002738:Chloroquine / Q000633:toxicity*; D004195:Disease Models, Animal; D005145:Face / Q000294:innervation / Q000503:physiopathology; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D056347:Neuroanatomical Tract-Tracing Techniques; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D011537:Pruritus / Q000139:chemically induced / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D012867:Skin / Q000187:drug effects / Q000294:innervation* / Q000503:physiopathology; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*
chemical_list: C494994:Gfra3 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D002738:Chloroquine; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium
keywords: GDNF family receptor α3 (GFRα3); Pruritus; Ret; epidermis; glial cell–derived neurotrophic factor (GDNF); hyperinnervation; xerosis
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