New Insight in Cold Pain: Role of Ion Channels, Modulation, and Clinical Perspectives

Lolignier, Stéphane; Gkika, Dimitra; Andersson, David A.; Leipold, Enrico; Vetter, Irina; Viana, Félix; Noël, Jacques; Busserolles, Jérôme

doi:10.1523/jneurosci.2327-16.2016

Cited by 57 publications

(39 citation statements)

References 55 publications

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“…TRPA1 was initially proposed to be involved in noxious cold sensing (Story et al 2003) but recent reports have questioned its role, hypothesizing that it might be regulating cold sensitivity indirectly, rather than acting as a cold-sensing receptor (Lolignier et al 2016;Yarmolinsky et al 2016;Winter et al 2017). If TRESK and TRPA1 are partially co-expressed in some neurons, one would expect an increase in the responses triggered by TRPA1 activation but, to our surprise, we observed the opposite effect despite TRPA1 mRNA expression being unchanged.…”

Section: Discussioncontrasting

confidence: 57%

“…) but recent reports have questioned its role, hypothesizing that it might be regulating cold sensitivity indirectly, rather than acting as a cold‐sensing receptor (Lolignier et al . ; Yarmolinsky et al . ; Winter et al .…”

Section: Discussionmentioning

confidence: 99%

“…Thermosensitivity to low temperatures is governed by different mechanisms and by distinct neuronal subpopulations than warm/hot perception (Lolignier et al 2016). We evaluated the role of TRESK in the cold sensitivity of C-fibres by recording fibre activity with the saphenous nerve preparation upon cooling their receptive fields in the skin from 30 to 10°C over 90 s (Fig.…”

Section: Elevated Perception Of Low Temperatures In the Absence Of Trmentioning

confidence: 99%

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

Castellanos

Pujol-Coma

Andrés‐Bilbé

et al. 2020

The Journal of Physiology

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Key points TRESK background K+ channel is expressed in sensory neurons and acts as a brake to reduce neuronal activation. Deletion of the channel enhances the excitability of nociceptors. Skin nociceptive C‐fibres show an enhanced activation by cold and mechanical stimulation in TRESK knockout animals. Channel deletion selectively enhances mechanical and cold sensitivity in mice, without altering sensitivity to heat. These results indicate that the channel regulates the excitability of specific neuronal subpopulations involved in mechanosensitivity and cold‐sensing. Abstract Background potassium‐permeable ion channels play a critical role in tuning the excitability of nociceptors, yet the precise role played by different subsets of channels is not fully understood. Decreases in TRESK (TWIK‐related spinal cord K+ channel) expression/function enhance excitability of sensory neurons, but its role in somatosensory perception and nociception is poorly understood. Here, we used a TRESK knockout (KO) mouse to address these questions. We show that TRESK regulates the sensitivity of sensory neurons in a modality‐specific manner, contributing to mechanical and cold sensitivity but without any effect on heat sensitivity. Nociceptive neurons isolated from TRESK KO mice show a decreased threshold for activation and skin nociceptive C‐fibres show an enhanced activation by cold and mechanical stimulation that was also observed in behavioural tests in vivo. 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 the channel regulates the excitability of specific neuronal subpopulations involved in mechanosensitivity and cold‐sensing, acting as a brake to prevent activation by innocuous stimuli.

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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Elevated Perception Of Low Temperatures In the Absence Of Trmentioning

confidence: 99%

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

Castellanos

Pujol-Coma

Andrés‐Bilbé

et al. 2020

The Journal of Physiology

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“…This is consistent with the notion that other nociceptors, such as polymodal nociceptors, may also be responsive to noxious doses of menthol. A recent review suggested that a variety of other TRP, potassium and sodium channels may be involved in the transduction or modulation of cold pain from peripheral afferents (Lolignier et al, 2016). However, it is unclear if any of these channels could be directly activated by menthol in the absence of TRPM8.…”

Section: Discussionmentioning

confidence: 99%

Select noxious stimuli induce changes on corneal nerve morphology

Hegarty

Hermes

Yang

et al. 2017

J of Comparative Neurology

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The surface of the cornea contains the highest density of nociceptive nerves of any tissue in the body. These nerves are responsive to a variety of modalities of noxious stimuli and can signal pain even when activated by low threshold stimulation. Injury of corneal nerves can lead to altered nerve morphology, including neuropathic changes which can be associated with chronic pain. Emerging technologies that allow imaging of corneal nerves in vivo are spawning questions regarding the relationship between corneal nerve density, morphology, and function. We tested whether noxious stimulation of the corneal surface can alter nerve morphology and neurochemistry. We used concentrations of menthol, capsaicin, and hypertonic saline that evoked comparable levels of nocifensive eye wipe behaviors when applied to the ocular surface of an awake rat. Animals were sacrificed and corneal nerves were examined using immunocytochemistry and three-dimensional volumetric analyses. We found that menthol and capsaicin both caused a significant reduction in corneal nerve density as detected with β-tubulin immunoreactivity 2 hr after stimulation. Hypertonic saline did not reduce nerve density, but did cause qualitative changes in nerves including enlarged varicosities that were also seen following capsaicin and menthol stimulation. All three types of noxious stimuli caused a depletion of CGRP from corneal nerves, indicating that all modalities of noxious stimuli evoked peptide release. Our findings suggest that studies aimed at understanding the relationship between corneal nerve morphology and chronic disease may also need to consider the effects of acute stimulation on corneal nerve morphology.

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“…These contradictory effects of cold in warm-blooded animals may be due to differences at the molecular, cellular, or circuit level (Vriens et al, 2014; Palkar et al, 2015; Lolignier et al, 2016). At the molecular level, temperature-sensitive transient receptor potential (thermoTRP) channels such as TRPM8 and TRPA1 have been reported to detect cold temperatures (Talavera et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

TRPA1 expression levels and excitability brake by K V channels influence cold sensitivity of TRPA1-expressing neurons

et al. 2017

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The molecular sensor of innocuous (painless) cold sensation is well-established to be Transient Receptor Potential cation channel, subfamily M, member 8 (TRPM8). However, the role of Transient Receptor Potential cation channel, subfamily A, member 1 (TRPA1) in noxious (painful) cold sensation has been controversial. We find that TRPA1 channels contribute to the noxious cold sensitivity of mouse somatosensory neurons, independent of TRPM8 channels, and that TRPA1-expressing neurons are largely non-overlapping with TRPM8-expressing neurons in mouse dorsal-root ganglia (DRG). However, relatively few TRPA1-expressing neurons (e.g., responsive to allyl isothiocyanate or AITC, a selective TRPA1 agonist) respond overtly to cold temperature in vitro, unlike TRPM8-expressing neurons, which almost all respond to cold. Using somatosensory neurons from TRPM8 −/− mice and subtype-selective blockers of TRPM8 and TRPA1 channels, we demonstrate that responses to cold temperatures from TRPA1-expressing neurons are mediated by TRPA1 channels. We also identify two factors that affect the cold-sensitivity of TRPA1-expressing neurons: 1) Cold-sensitive AITC-sensitive neurons express relatively more TRPA1 transcripts than cold-insensitive AITC-sensitive neurons and 2) voltage-gated potassium (KV) channels attenuate the cold-sensitivity of some TRPA1-expressing neurons. The combination of these two factors, combined with the relatively weak agonist-like activity of cold temperature on TRPA1 channels, partially explains why few TRPA1-expressing neurons respond to cold. Blocking KV channels also reveals another subclass of noxious cold-sensitive DRG neurons that do not express TRPM8 or TRPA1 channels. Altogether, the results of this study provide novel insights into the cold-sensitivity of different subclasses of somatosensory neurons.

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New Insight in Cold Pain: Role of Ion Channels, Modulation, and Clinical Perspectives

Cited by 57 publications

References 55 publications

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

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

Select noxious stimuli induce changes on corneal nerve morphology

TRPA1 expression levels and excitability brake by K V channels influence cold sensitivity of TRPA1-expressing neurons

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New Insight in Cold Pain: Role of Ion Channels, Modulation, and Clinical Perspectives

Cited by 57 publications

References 55 publications

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

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

Select noxious stimuli induce changes on corneal nerve morphology

TRPA1 expression levels and excitability brake by K V channels influence cold sensitivity of TRPA1-expressing neurons

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

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