title: Synergistic antipruritic effects of gamma aminobutyric acid A and B agonists in a mouse model of atopic dermatitis.
abstract: BACKGROUND
  Despite recent insights into the pathophysiology of acute and chronic itch, chronic itch remains an often intractable condition. Among major contributors to chronic itch is dysfunction of spinal cord gamma aminobutyric acidergic (GABAergic) inhibitory controls.
  
  
  OBJECTIVE
  We sought to test the hypothesis that selective GABA agonists as well as cell transplant-derived GABA are antipruritic against acute itch and in a transgenic mouse model of atopic dermatitis produced by overexpression of the TH2 cell-associated cytokine, IL-31 (IL-31Tg mice).
  
  
  METHODS
  We injected wild-type and IL-31Tg mice with combinations of GABA-A (muscimol) or GABA-B (baclofen) receptor agonists 15 to 20 minutes prior to injection of various pruritogens (histamine, chloroquine, or endothelin-1) and recorded spontaneous scratching before and after drug administration. We also tested the antipruritic properties of intraspinal transplantation of precursors of GABAergic interneurons in the IL-31Tg mice.
  
  
  RESULTS
  Systemic muscimol or baclofen are antipruritic against both histamine-dependent and -independent pruritogens, but the therapeutic window using either ligand alone was very small. In contrast, combined subthreshold doses of baclofen and muscimol produced a significant synergistic antipruritic effect, with no sedation. Finally, transplant-mediated long-term enhancement of GABAergic signaling not only reduced spontaneous scratching in the IL-31Tg mice but also dramatically resolved the associated skin lesions.
  
  
  CONCLUSIONS
  Although additional research is clearly needed, existing approved GABA agonists should be considered in the management of chronic itch, notably atopic dermatitis.
authors.affiliation: Department of Anatomy, University California San Francisco, San Francisco, Calif; Department of Dermatology, University California San Francisco, San Francisco, Calif.
authors.forename: Ferda
authors.initials: F
authors.lastname: Cevikbas
authors.affiliation: Department of Anatomy, University California San Francisco, San Francisco, Calif. Electronic address: joao.braz2@ucsf.edu.
authors.forename: Joao M
authors.initials: JM
authors.lastname: Braz
authors.affiliation: Department of Anatomy, University California San Francisco, San Francisco, Calif.
authors.forename: Xidao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Anatomy, University California San Francisco, San Francisco, Calif.
authors.forename: Carlos
authors.initials: C
authors.lastname: Solorzano
authors.affiliation: Department of Dermatology, University California San Francisco, San Francisco, Calif; Department of Dermatology, University Hospital Münster, Münster, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Sulk
authors.affiliation: Department of Dermatology, University California San Francisco, San Francisco, Calif; Department of Dermatology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Buhl
authors.affiliation: Department of Dermatology, University California San Francisco, San Francisco, Calif; Department of Dermatology, University College Dublin, Dublin, Ireland; Charles Institute for Translational Dermatology, University College Dublin, Dublin, Ireland; Department of Dermatology and Venerology, Hamad Medical Corporation, Qatar University, Doha, Qatar; School of Medicine, Qatar University, Doha, Qatar.
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
authors.affiliation: Department of Anatomy, University California San Francisco, San Francisco, Calif.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Basbaum
mesh_terms: D000818:Animals; D000982:Antipruritics / Q000627:therapeutic use*; D001418:Baclofen / Q000627:therapeutic use*; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy; D004195:Disease Models, Animal; D004357:Drug Synergism; D058785:GABA-A Receptor Agonists / Q000627:therapeutic use*; D058786:GABA-B Receptor Agonists / Q000627:therapeutic use*; D019886:Gastrin-Releasing Peptide / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000235:genetics; D007378:Interleukins / Q000235:genetics; D007395:Interneurons / Q000187:drug effects; D008297:Male; D008473:Median Eminence / Q000166:cytology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009118:Muscimol / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D018004:Receptors, Bombesin / Q000235:genetics; D011963:Receptors, GABA-A / Q000235:genetics; D018080:Receptors, GABA-B / Q000235:genetics; D018040:Receptors, Neurokinin-1 / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D033581:Stem Cell Transplantation
chemical_list: D000982:Antipruritics; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D007378:Interleukins; D012333:RNA, Messenger; D018004:Receptors, Bombesin; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D018040:Receptors, Neurokinin-1; C502588:interleukin-31, mouse; D009118:Muscimol; D019886:Gastrin-Releasing Peptide; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2; D001418:Baclofen
keywords: Atopic dermatitis; GABA; GABAergic progenitor cell transplants; baclofen; chronic itch; muscimol; pruritogens