Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons

Dhandapani, Rahul; Arokiaraj, Cynthia M.; Taberner, Francisco J.; Pacifico, Paola; Raja, Sruthi; Nocchi, Linda; Portulano, Carla; Franciosa, Federica; Maffei, Mariano; Hussain, Ahmad Fawzi; Reis, Fernanda de Castro; Reymond, Luc; Perlas, Emerald; Garcovich, Simone; Barth, Stefan; Johnsson, Kai; Lechner, Stefan; Heppenstall, Paul A.

doi:10.1038/s41467-018-04049-3

Cited by 100 publications

(103 citation statements)

References 66 publications

(86 reference statements)

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“…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. The Piezo2 channel is involved in the detection of both innocuous touch and high-threshold noxious mechanical stimuli due to its expression in low-threshold mechanoreceptors (LTMRs) and nociceptors (Ranade et al 2014;Dhandapani et al 2018;Murthy et al 2018;Szczot et al 2018), and has been proposed to play a crucial role in the generation of mechanical allodynia during inflammation and neuropathic pain (Murthy et al 2018). TRESK is also highly expressed in these populations of sensory neurons involved in mechanical hypersensitivity (Usoskin et al 2015).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Nevertheless, the unique physiological properties of the glabrous skin Dhair receptor suggest that these hairs serve a distinct and specific sensory role in comparison to the hairy skin D-hair receptors. Recently, several reports in mice have suggested that it is D-hair receptors that drive touch evoked pain under neuropathic conditions (Dhandapani et al, 2018;Peng et al, 2017;Ventéo et al, 2016). Since in neuropathic models behavioral assessments of increased sensitivity to mechanical stimuli are made using von Frey hairs applied to the glabrous skin of the hind paw, it is likely that glabrous skin D-hair receptors drive neuropathic behavior.…”

Section: Discussionmentioning

confidence: 99%

Specialized mechanoreceptor systems in rodent glabrous skin

Lewin

Walcher

Ojeda-Alonso

et al. 2018

Preprint

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Rodents use their forepaws to actively interact with their tactile environment. Studies on the physiology and anatomy of glabrous skin that makes up the majority of the forepaw are almost non-existent in the mouse. Here we developed a preparation to record from single sensory fibers of the forepaw and compared anatomical and physiological receptor properties to those of the hind paw glabrous and hairy skin. We found that the mouse forepaw skin is equipped with a very high density of mechanoreceptors; >3 fold more than hind paw glabrous skin. In addition, rapidly adapting mechanoreceptors that innervate Meissner's corpuscles of the forepaw were several-fold more sensitive to slowly moving mechanical stimuli compared to their counterparts in the hind paw glabrous skin. All other mechanoreceptors types as well as myelinated nociceptors had physiological properties that were invariant regardless of which skin area they occupied. We discovered a novel D-hair receptor innervating a small group of hairs in the middle of the hind paw glabrous skin in mice. Glabrous D-hair receptors were direction sensitive albeit with an orientation sensitivity opposite to that described for hairy skin D-hair receptors. Glabrous D-hair receptors do not occur in all rodents, but are present in North American and African rodent species that diverged more than 65 million years ago. The function of these specialized hairs is unknown, but they are nevertheless evolutionarily very ancient. Our study reveals novel physiological specializations of mechanoreceptors in the glabrous skin that likely evolved to facilitate tactile exploration.

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“…This effect was not linked to gender, since both male and female animals showed similar responses. Piezo2 channel is involved in the detection of both innocuous touch and high threshold noxious mechanical stimuli due to its expression in low threshold mechanoreceptors (LTMR) and nociceptors (Murthy et al 2018;Szczot et al 2018;Dhandapani et al 2018;Ranade et al 2014), and has been proposed to play a crucial role in the generation of mechanical allodynia during inflammation and neuropathic pain states (Murthy et al 2018). TRESK is also highly expressed in these populations of sensory neurons involved in mechanical hypersensitivity (Usoskin et al 2015).…”

Section: Interestingly Deleting Both Channels (Trek-1/traak Double Kmentioning

confidence: 99%

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

Castellanos

Pujol-Coma

Andrés‐Bilbé

et al. 2019

Preprint

View full text Add to dashboard Cite

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.

show abstract

Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons

Cited by 100 publications

References 66 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

Specialized mechanoreceptor systems in rodent glabrous skin

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

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Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons

Cited by 100 publications

References 66 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

Specialized mechanoreceptor systems in rodent glabrous skin

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

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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

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