Background & Aims
The TREK1 potassium channel plays a crucial role in polymodal pain and morphine-induced analgesia. Several studies show that pharmacological activation of this channel produces analgesia in different rodent pain models. Yet, TREK1 is expressed in both the peripheral and central nervous systems, raising uncertainty about whether selectively targeting peripheral TREK1, considered safer due to the widespread central expression of this channel, is sufficient to induce pain relief.
Methods
To investigate the contribution of peripheral TREK1 channels in nociception, we measured calcium transients produced in response to capsaicin with/without co-treatment with the TREK1 activator ML335 in cultured sensory neurons from WT, TREK1 knock-out and TREK1-Tomato Cre-dependent reporter mice. Sensitivity to noxious heat was also evaluated in vivo in TREK1 global and conditional knockouts (restricted to Nav1.8-positive neurons).
Results
Immunostaining of TRPV1 in DRG slices from TREK1-Tomato mice revealed that 56% of TREK1-positive neurons express TRPV1 and 16% of TRPV1-positive neurons express TREK1. ML335 treatment decreased the average intensity of calcium transients triggered by capsaicin in cultured DRG neurons, while neurons from TREK1 knockout mice exhibited a higher response to capsaicin. Also, over 90% of TREK1-positive neurons responded to capsaicin, supporting the role of TREK1 channels in reducing the excitability of a population of putative heat-sensitive nociceptors. In vivo, we confirmed that TREK1 global knockout mice are more sensitive to noxious heat (46°C) than wild-type mice. Conditional (Nav1.8-Cre) TREK1 knockouts show intermediate pain thresholds, suggesting that TREK1 channels in nociceptors are necessary but not sufficient for thermonociception. Conclusion. Our findings highlight the involvement of TREK1 in heat sensitivity, implicating a reduction of nociceptors excitability at the periphery together with a contribution of central TREK1 channels that remains to be explored.
Conclusions
Our findings highlight the involvement of TREK1 in heat sensitivity, implicating a reduction of nociceptors excitability at the periphery together with a contribution of central TREK1 channels that remains to be explored.
References
(Alloui et al. 2006; Devilliers et al. 2013; Coderre et al. 2007; Hama et Sagen 2011; Qiu et al. 2020; Busserolles et al. 2020; Ávalos Prado et al. 2021)
Presenting Author
Romane Boyer
Poster Authors
Romane Boyer
PhD
Université Clermont-Auvergne, Clermont-Ferrand, France
Lead Author
Stéphane Lolignier
Université Clermont-Auvergne, Clermont-Ferrand, France
Lead Author
Topics
- Mechanisms: Biological-Molecular and Cell Biology