TRESK background potassium channel in MrgprA3 + pruriceptors regulates acute and chronic itch
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (Arcadia Science)
Abstract
TRESK (K2P18.1) is a background K + channel expressed in sensory neurons, where it modulates the resting membrane potential, action potential firing and neuronal excitability. A subset of these sensory neurons, which express specific TRPs and Mas-related G protein-coupled receptors (Mrgprs), are activated by pruritogens and mediate itch sensations. Because TRESK is involved in somatosensation and pain transduction, we evaluated the contribution of this channel to pruritic sensitivity and its potential as a target for the treatment of chronic itch pathologies. By combining RNA in situ hybridization, calcium imaging, electrophysiological and behavioral approaches, we found that TRESK is involved in the modulation of non-histaminergic itch. TRESK is coexpressed with MrgprD + and MrgprA3 + in sensory neurons and MrgprA3 + neurons from TRESK -/- animals display an enhanced firing compared to WT counterparts. Interestingly, acute itch to intradermal injection of chloroquine is significantly enhanced in the absence of TRESK but not the response to histamine, BAM8-22 or LTC4. TRESK deletion also enhanced chronic itch in mice models of Allergic Contact Dermatitis and Dry Skin. In the mouse model imiquimod-induced psoriasiform dermatitis, the absence of TRESK produced a significantly enhanced scratching behavior, which developed earlier and was more robust. Finally, enhancing TRESK function with the channel activator cloxyquin diminished both acute and chronic itch in WT mice but not in KO animals. In summary, our data indicates that TRESK is involved in regulating the excitability of a subset of sensory neurons that mediate histaminergic-independent itch. Enhancing the channel function with specific activators constitutes a novel anti-pruritic therapeutic method that can be combined with other compounds for the treatment of non-histaminergic itch, for which appropriate treatments are lacking.
Article activity feed
-
olive oil (vehicle)
Did you notice any inflammatory or adjuvant effect from the olive oil?
-
Moreover, although we only tested a single cloxyquin concentration applied 2h before the pruritic challenge, the data demonstrates that TRESK activation can be employed to alleviate pruritus and further underscore the role of this channel modulating pruriceptor excitability
This is a nice proof-of-principle application for TRESK agonists to treat acute and chronic pruritus. It will be interesting to see how long TRESK agonists effects last after initial or repeated treatments--is the effect longer term than 2 hours?
-
Intraperitoneal injection of cloxyquin (50 mg/Kg) or its vehicle (olive oil), administered two hours before the pruritic test did not induce any significant scratching in wild-type mice
I'm curious if activation of TRESK, though single or repeated injection of cloxyquin, resulted in any phenotypes other than reducing pruritus (concomitant reduction in cold or mechanical sensitivity, or a change in any migraine-like pain-associated behavior.)?
-
The number of scratching bouts towards the injection site during 15-minute periodwas counted.
This is a very exciting study overall, and I'm really interested in the mechanistic interaction between the TRESK channel and MrgprA3+ prurireceptors. For the cheek itch assay, it would be great to know whether scratching bouts were counted manually from videos, or whether you used another technique. Thanks!
-
