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J Allergy Clin Immunol. 2017 Aug;140(2):454-464.e2. doi: 10.1016/j.jaci.2017.02.001. Epub 2017 Feb 21.

Synergistic antipruritic effects of gamma aminobutyric acid A and B agonists in a mouse model of atopic dermatitis.

Author information

1
Department of Anatomy, University California San Francisco, San Francisco, Calif; Department of Dermatology, University California San Francisco, San Francisco, Calif.
2
Department of Anatomy, University California San Francisco, San Francisco, Calif. Electronic address: joao.braz2@ucsf.edu.
3
Department of Anatomy, University California San Francisco, San Francisco, Calif.
4
Department of Dermatology, University California San Francisco, San Francisco, Calif; Department of Dermatology, University Hospital Münster, Münster, Germany.
5
Department of Dermatology, University California San Francisco, San Francisco, Calif; Department of Dermatology, University Medical Center Göttingen, Göttingen, Germany.
6
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.

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.

OBJECTIVES:

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.

KEYWORDS:

Atopic dermatitis; GABA; GABAergic progenitor cell transplants; baclofen; chronic itch; muscimol; pruritogens

PMID:
28232084
PMCID:
PMC5546982
DOI:
10.1016/j.jaci.2017.02.001
[Indexed for MEDLINE]
Free PMC Article

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