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 GABAergic inhibitory controls. Objective 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 15–20 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. 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. Conclusion Although additional research is clearly needed, existing approved GABA agonists should be considered in the management of chronic itch, notably atopic dermatitis.

Circuit dissection of the role of somatostatin in itch and pain

“…Our results reveal that they act on distinct neural substrates and that the pathways engaged by these transmitters, although initially separate, converge and interact ( Figure 3 , 4 , and 6 ). Although somatostatin presumably acts at least partly through dynorphin/KOR signaling to regulate itch, inhibition involving GABA and glycine has also been shown to play a critical role in suppressing pruritogen-evoked activity 31 , 42 , 43 . GABA, the principal fast transmitter used by the dynorphin/galanin interneurons 44 , is therefore also likely to have contributed to the anti-pruritic effect of stimulating the dynorphin neurons, and to be involved in somatostatin-evoked itch.…”

Neuroimmune interactions in chronic itch of atopic dermatitis

“…Several studies have demonstrated that loss of GABAergic interneurons or downregulation of a GABA receptor subunit is essential for chronic itch in mice, suggesting GABA agonists could effectively treat itch in AD patients as well. [31][32][33]…”

“…Transmission of pruritoceptive signals via GPRP+ spinal cord neurons is regulated by inhibitory gamma‐aminobutyric acid (GABA)ergic interneurons. Several studies have demonstrated that loss of GABAergic interneurons or downregulation of a GABA receptor subunit is essential for chronic itch in mice, suggesting GABA agonists could effectively treat itch in AD patients as well …”

Brain allopregnanolone induces marked scratching behaviour in diet-induced atopic dermatitis mouse model

“…(1) ALLO-induced scratching was not mediated through spinal GABA A receptors, although the effects on the receptors in the central nucleus of the amygdala could not be excluded. (2) In the previous studies, muscimol was used as an agonist for GABA A receptors to inhibit scratching responses 45,46 . On the other hand, ALLO caused scratching probably by pharmacological properties that differed from those of muscimol (as described above), whereas muscimol similarly reduced scratching in our model 10 .…”