Itch suppression in mice and dogs by modulation of spinal α2 and α3GABAA receptors

Abstract

Chronic itch is a highly debilitating condition affecting about 10% of the general population. The relay of itch signals is under tight control by inhibitory circuits of the spinal dorsal horn, which may offer a hitherto unexploited therapeutic opportunity. Here, we found that specific pharmacological targeting of inhibitory α2 and α3GABAA receptors reduces acute histaminergic and non-histaminergic itch in mice. Systemic treatment with an α2/α3GABAA receptor selective modulator alleviates also chronic itch in a mouse model of atopic dermatitis and in dogs sensitized to house dust mites, without inducing sedation, motor dysfunction, or loss of antipruritic activity after prolonged treatment. Transsynaptic circuit tracing, immunofluorescence, and electrophysiological experiments identify spinal α2 and α3GABAA receptors as likely molecular targets underlying the antipruritic effect. Our results indicate that drugs targeting α2 and α3GABAA receptors are well-suited to alleviate itch, including non-histaminergic chronic itch for which currently no approved treatment exists.

Role of SNAREs in Atopic Dermatitis–Related Cytokine Secretion and Skin-Nerve Communication

“…Thus, peripheral BNP may play a significant role in modulating inflammatory response in the skin during AD. Recent papers support this notion by showing that BNP is implicated in AD transmission in dog and mouse itch models (Pitake et al, 2018;Ralvenius et al, 2018). Altogether, our study adds insights into the itch circuits in the neuron-skin communications (Graphical Abstract).…”

The α2/α3GABAA receptor modulator TPA023B alleviates not only the sensory but also the tonic affective component of chronic pain in mice

“…or with vehicle. The doses were chosen based on a previous study with well-established dose-response curves 35. TPA023B exerted a dose-dependent antihyperalgesic action expressed as percent maximum possible effect (mechanical hyperalgesia: 30.4 6 3.9% and 67.2 6 4.0%, for 0.3 mg/kg and 1 mg/kg TPA023B, respectively; heat hyperalgesia: 65.1 6 7.7% and 122.2 6 12.2%, for 0.3 mg/kg and 1 mg/kg TPA023B,…”

The α2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats

“…However, we have not done experiments here to define either the specific neuronal populations from which the recordings were made or the presence of GABA A receptors containing 2/3 subunits on these neurons or on innovating neurons. If some of the sensory neurons recorded were nociceptors, there is evidence for the presence of 2-and 3-containing GABA A receptors on those neurons and for their involvement in pain perception (Lian et al, 2012;Lorenzo et al, 2014;Paul et al, 2014;Ralvenius et al, 2018;Witschi et al, 2011). The potency of KRM-II-81 was about an order of magnitude greater in DRG neurons than in human recombinant receptors in our study.…”