TRESK K⁺Channel Activity Regulates Trigeminal Nociception and Headache

Abstract

Although TWIK-related spinal cord K + (TRESK) channel is expressed in all primary afferent neurons in trigeminal ganglia (TG) and dorsal root ganglia (DRG), whether TRESK activity regulates trigeminal pain processing is still not established. Dominant-negative TRESK mutations are associated with migraine but not with other types of pain in humans, suggesting that genetic TRESK dysfunction preferentially affects the generation of trigeminal pain, especially headache. Using TRESK global knock-out mice as a model system, we found that loss of TRESK in all TG neurons selectively increased the intrinsic excitability of small-diameter nociceptors, especially those that do not bind to isolectin B4 (IB4 − ). Similarly, loss of TRESK resulted in hyper-excitation of the small IB4 − dural afferent neurons but not those that bind to IB4 (IB4 + ). Compared with wild-type littermates, both male and female TRESK knock-out mice exhibited more robust trigeminal nociceptive behaviors, including headache-related behaviors, whereas their body and visceral pain responses were normal. Interestingly, neither the total persistent outward current nor the intrinsic excitability was altered in adult TRESK knock-out DRG neurons, which may explain why genetic TRESK dysfunction is not associated with body and/or visceral pain in humans. We reveal for the first time that, among all primary afferent neurons, TG nociceptors are the most vulnerable to the genetic loss of TRESK. Our findings indicate that endogenous TRESK activity regulates trigeminal nociception, likely through controlling the intrinsic excitability of TG nociceptors. Importantly, we provide evidence that genetic loss of TRESK significantly increases the likelihood of developing headache.

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

“…Our data suggest that the lack of TRESK enhances cold sensitivity by increasing the percentage of C-fibres activated at moderate cold, which is translated at the behavioural level by an enhanced sensitivity to cold stimuli. An increase in cold sensitivity has also been reported in TRESK KO mice using the acetone test (Guo et al 2019). In our study, the fraction of C-fibres activated by cold (C-MHC and C-MC; 58% in WT mice) was higher than other reports (35-45%), which could be due to the smaller number of fibres sampled compared to other studies Noël et al 2009;Pereira et al 2014;Winter et al 2017) but, as occurred after deletion of other K 2P channels, the fraction of cold-sensitive C-fibres was enhanced in TRESK KO mice compared to WT animals.…”

“…Another study reported similar results in TG neurons but, surprisingly, lumbar DRG neurons from the same TRESK KO mice were not found to be hyperexcitable (Guo et al . ). Although we did not differentiate between IB4 + and IB4 − neurons in this study, our data support previous findings of enhanced excitability of nociceptive sensory neurons (small DRGs) either after TRESK deletion or after a significant decrease in its expression (Dobler et al .…”

“…An increase in cold sensitivity has also been reported in TRESK KO mice using the acetone test (Guo et al . ). In our study, the fraction of C‐fibres activated by cold (C‐MHC and C‐MC; 58% in WT mice) was higher than other reports (35–45%), which could be due to the smaller number of fibres sampled compared to other studies (Bautista et al .…”

“…A decrease in the withdrawal threshold to application of von Frey filaments in the forehead skin (trigeminal area) has also been reported but, surprisingly, not in the hindpaw (Guo et al . ). In our study, mechanical sensitivity is enhanced by shifting the mechanical threshold toward lower values in a population of sensory fibres, and therefore, a higher number of fibres is activated by low‐intensity mechanical stimulation.…”

“…Therefore, the enhanced cold sensitivity in TRESK KO mice does not seem related to activation of TRPM8 + fibres. Nevertheless, TRPM8 + /IB4 − trigeminal neurons have been reported to be more excitable in the TRESK KO compared with WT neurons (Guo et al 2019), and thus an increase in activation of TRPM8 + fibres after TRESK deletion cannot be completely discarded. Recently, a new cold sensor (GLR-3) has been identified in Caenorhabditis elegans and the kainate receptor GluK2 (mouse GLR-3 homolog) has been proposed to mediate cold sensitivity in mouse DRGs (Gong et al 2019).…”