Synergistic antipruritic effects of GABA-A and GABA-B agonists in a mouse model of atopic dermatitis

Publication date: Available online 21 February 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Ferda Cevikbas, Joao M. Braz, Xidao Wang, Carlos Solorzano, Mathias Sulk, Timo Buhl, Martin Steinhoff, Allan I. Basbaum
BackgroundDespite 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 GABAergic inhibitory controls.ObjectiveTo 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).MethodsWe injected wild-type and IL-31Tg mice with combinations of GABA-A (muscimol) or GABA-B (baclofen) receptor agonists 15-20 min 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.ResultsSystemic 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.ConclusionAlthough additional research is clearly needed, existing approved GABA agonists should be considered in the management of chronic itch, notably atopic dermatitis.Clinical implicationsPreclinical data encourage the design of human studies to explore the use of GABA-agonists, such as FDA-approved baclofen in the management of acute and chronic itch.

Teaser

Selective GABA-A (muscimol) and GABA-B (baclofen) receptor agonists, have profound, synergistic antipruritic properties against both acute itch and in a mouse model of atopic dermatitis.


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