Ferda Cevikbas, PhD,a,b* Joao M. Braz, PhD,a* Xidao Wang, PhD,a Carlos Solorzano, PhD,a Mathias Sulk, MD,b,c
Timo Buhl, MD,b,d Martin Steinhoff, PhD,b,e,f,g,h and Allan I. Basbaum, PhDa
Atopic dermatitis (AD), an inflammatory, relapsing chronic
pruritic skin disease, is an often intractable form of chronic itch
that negatively impacts the quality of life of millions of patients.1
Unfortunately, because chronic itch conditions have very
different etiologies, most treatments have poor outcomes and
are accompanied by unacceptable adverse side effects, notably
sedation.2 Clearly, a better understanding of the pathophysiology
of these chronic itch conditions is critical to designing successful
therapeutic strategies.
Studies of the etiology of chronic itch3 generally focus on
changes in skin and immune dysfunction. However, there is
now considerable evidence for a contribution of primary afferent
pruritoceptors that transmit itch messages to spinal cord and
brainstem circuits engaged by and that regulate these messages.4
Of particular interest are studies demonstrating commonalities in
the mechanisms underlying nerve injury-induced neuropathic
pain and itch and the possibility that comparable approaches
may be appropriate for their management.5
Although there is evidence for specificity in the transmission of
itch and pain messages at the level of the primary afferent
nociceptor and pruritoceptor,6,7 both pain and itch are under
spinal cord inhibitory interneuron-mediated control. For example,
loss of spinal cord gamma aminobutyric acid (GABA) or glycinergic
function is a major contributor to the spontaneous pain and hypersensitivity
that develops following nerve injury.8-10 Moreover,
persistent scratching, a manifestation of chronic itch, occurs in the
Bhlhb5 mutant mouse, in which there is dramatic loss of dorsal
horn GABAergic inhibitory interneurons.11 Ablation of glycinergic
interneurons also induces excessive scratching and pain.12
And in a model of dry skin–induced scratching in the mouse,
GABA and glycine receptor antagonists can block scratchinginduced
inhibition of firing in superficial dorsal horn neurons.13
Finally, in patients, acute withdrawal of intrathecal baclofen, a
GABA-B receptor agonist, can induce pruritus.14
Given the evidence for a potential contribution of GABA
agonists in the management of pruritus, it is surprising that there
are no studies that assessed their utility in preclinical or clinical
conditions. Here, we demonstrate that both GABA-A and
GABA-B agonists are not only effective in models of acute itch,
but we also show that systemic administration of very low doses
of these agonists has synergistic antipruritic effects in IL-31
overexpressing transgenic mouse, a model of AD15 that is refractory
to antihistamines1,16 and thus particularly difficult to
manage. Most importantly, the antipruritic synergy could be produced
without concomitant sedation. Finally, we show that sustaining
high levels of GABA inhibition can be achieved using
intraspinal transplantation of cortical GABAergic interneuron
precursor cells. The transplants not only attenuated spontaneous
scratching but also dramatically reduced skin lesions in the IL-
31 overexpressing transgenic mouse (IL-31Tg) mice.
