TRESK background K⁺ channel deletion selectively uncovers enhanced mechanical and cold sensitivity

Abstract

Changes in TRESK K + channel expression/function enhance sensory neurons excitability, but its role in somatosensory perception and nociception is poorly understood. We show that TRESK regulates the sensitivity to mechanical and cold stimuli but not the perception of heat. TRESK knockout mice nociceptive neurons present an enhanced excitability; skin nociceptive C-fibers show an increased activation by lower intensity cold or mechanical stimulation and mice lacking TRESK present mechanical and cold hypersensitivity. TRESK is also involved in osmotic pain and in early phases of formalin-induced inflammatory pain, but not in the development of mechanical and heat hyperalgesia during chronic pain. In contrast, mice lacking TRESK present cold allodynia that is not further enhanced by oxaliplatin. In summary, genetic removal of TRESK uncovers enhanced mechanical and cold sensitivity, indicating that it regulates the excitability of specific neuronal subpopulations involved in mechanosensitivity and cold-sensing, acting as a brake to prevent activation by low-intensity stimuli.

TRESK background potassium channel modifies the TRPV1-mediated nociceptor excitability in sensory neurons

“…The sensitivity of DRG neurons from wild-type and TRESK KO animals to a potent TRPV1 agonist, capsaicin, was determined by using cytoplasmic calcium imaging. There was no difference in the capsaicin sensitivity of wild-type and TRESK KO neurons, which is in good agreement with a recent study comparing the responses of wild-type and TRESK KO DRG neurons to various TRP channel agonists (32).…”

“…The K 2P channel TRESK is a major component of the background potassium current in the primary sensory neurons of the dorsal root and trigeminal ganglia. Accordingly, an increased sensitivity to various painful stimuli have been described in TRESK KO animals in different regions of the body (28)(29)(30)(31)(32) and reduced abundance of TRESK was associated with pathological pain conditions (33,34). A recent report suggested that trigeminal neurons are particularly sensitive to altered TRESK activity (29).…”

Peripheral kappa opioid receptor activation drives noxious cold hypersensitivity in mice

“…To determine whether KOR activation mediates temperature-dependent hypersensitivity, we recorded jumping behavior across a range of temperatures (3 o C, 10 o C, 15 o C, 20 o C, 30 o C, 42 o C) ( Fig 1A). Jumping behavior in this assay has been well-established as a measure of nocifensive behavior (Allchorne et al, 2005;Castellanos et al, 2020;Deuis et al, 2017). We show that the KOR agonist, U50 (5 mg/kg i.p.)…”

TRESK is a modality‐specific brake on nociceptor excitability

“…In this issue of The Journal of Physiology, Castellanos et al (2020) report the use of a global TRESK knockout (KO) mouse to explore the role of this channel in somatosensation. Their recordings form nociceptors isolated from TRESK KO mice confirmed previous observations that, despite displaying weaker K + current density, these neurons have a resting membrane potential that is very close to their wild-type (WT) littermates.…”

“…When the injected depolarizing currents exceeded the AP threshold, nociceptors of TRESK KO mice fired significantly more APs, indicating that the removal of TRESK increases the excitability of nociceptors. Castellanos et al (2020) then used a Ca imaging approach to examine the sensitivity of nociceptors to common agonists. Although the responses to capsaicin and menthol did not change, responsiveness to the TRPA1 agonist allyl isothiocyanate (AITC) was significantly reduced.…”