Therapeutic opportunities for targeting cold pain pathways

Yin, Kathleen; Zimmermann, Katharina; Vetter, Irina; Lewis, Richard J.

doi:10.1016/j.bcp.2014.09.024

Cited by 33 publications

(35 citation statements)

References 185 publications

(250 reference statements)

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“…In line with our results in sensory neurons innervating the skin and the mucosa, previous studies showed that a significant proportion of sensory neurons are activated by cold stimulation but are insensitive to TRPM8 and TRPA1 agonists 33,34 . The cold sensitive receptors expressed in these neurons have not been fully identified, but could include sodium and potassium channels such as eNaC, TREK1 and TRAAK, which genetic deletion and pharmacological blockade were shown to reduced cold-induced pain 35–37 .…”

Section: Discussionmentioning

confidence: 99%

TRPM8 and TRPA1 do not contribute to dental pulp sensitivity to cold

Michot

Lee

Gibbs

2018

Sci Rep

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Sensory neurons innervating the dental pulp have unique morphological and functional characteristics compared to neurons innervating other tissues. Stimulation of dental pulp afferents whatever the modality or intensity of the stimulus, even light mechanical stimulation that would not activate nociceptors in other tissues, produces an intense pain. These specific sensory characteristics could involve receptors of the Transient Receptor Potential channels (TRP) family. In this study, we compared the expression of the cold sensitive receptors TRPM8 and TRPA1 in trigeminal ganglion neurons innervating the dental pulp, the skin of the cheek or the buccal mucosa and we evaluated the involvement of these receptors in dental pulp sensitivity to cold. We showed a similar expression of TRPM8, TRPA1 and CGRP in sensory neurons innervating the dental pulp, the skin or the mucosa. Moreover, we demonstrated that noxious cold stimulation of the tooth induced an overexpression of cFos in the trigeminal nucleus that was not prevented by the genetic deletion of TRPM8 or the administration of the TRPA1 antagonist HC030031. These data suggest that the unique sensory characteristics of the dental pulp are independent to TRPM8 and TRPA1 receptors expression and functionality.

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Section: Discussionmentioning

confidence: 99%

TRPM8 and TRPA1 do not contribute to dental pulp sensitivity to cold

Michot

Lee

Gibbs

2018

Sci Rep

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“…Although many pathological pain conditions, including diabetic neuropathy, peripheral nerve injury, chemotherapy-induced neuropathy, poststroke central pain, or ciguatera poisoning, can result in the development of cold pain, the mechanisms by which cold pain arises are still poorly understood and appear to vary significantly in relation to the disease considered (for review, see Yin et al, 2015).…”

Section: Pathological Cold Pain Conditionsmentioning

confidence: 99%

“…Our current understanding of the mechanisms of thermal transduction is fairly incomplete, especially the transduction of cold stimuli that appears to involve different cold transducers, some of which are yet to be identified, and other ion channels playing an indirect role in this process by setting the electrophysiological environment required by the transduction machinery. Pathological cold pain, a common symptom in a range of neuropathic pain syndromes, may also arise from dysfunctions of this transduction machinery, and presents as cold allodynia, a pain response to cold temperatures that do not normally provoke pain, and/or cold hyperalgesia, an increased sensitivity to painful cold temperature (Yin et al, 2015). The aim of this review is to provide an overview of our current knowledge about the contribution of specific ions channels to physiological and pathological cold transduction and cold-triggered pain, emphasizing on the recent progress made in the understanding of the identity and respective roles and regulation of these channels.…”

mentioning

confidence: 99%

“…More recent studies have also shown a role for TRPM8 channels and TRPM8-expressing neurons in cold-triggered nociception (Knowlton et al, 2011;Pogorzala et al, 2013). Although TRPM8 involvement in non-noxious thermal discrim-ination Ͻ25°C is undisputable, its involvement in cold-triggered nociception remains debated (Yin et al, 2015). Whereas TRPM8 activation by cold as well as by exogenous substances such as menthol have been the matter of extensive studies (Almaraz et al, 2014), endogenous activators or inhibitors of TRPM8 have more rarely been identified.…”

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confidence: 99%

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

et al. 2016

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Cold temperature detection involves the process of sensory transduction in cutaneous primary sensory nerve terminals, which converts thermal stimuli into depolarizations of the membrane. This transformation into electrical signals is followed by the subsequent propagation of action potentials in cold-sensitive afferent nerve fibers. A large array of ion channels shapes this process; however, the precise contribution of specific ion channel subtypes to cold perception and cold pain remains elusive. This review aims at giving an update on our current understanding of the role played by TRPs, leak K ϩ and voltage-gated Na ϩ and K ϩ channels in the transduction of cold by nociceptors and in cold-induced pain.

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“…However, as with A-fibres, additional subclasses of C-fibre neurons exist, categorised by sensitivity to a diverse array of stimuli. Some of these C-fibre subclasses are sensitive to a single stimulus type (exclusively responsive to innocuous or noxious heat, cold, or mechanical stimuli [13][14][15][16] ), while others are polymodal nociceptors responding to multiple stimuli 6,17,18 . Select C-fibres groups are also activated by noxious chemical stimuli and inflammatory mediators 19 such as capsaicin 20 and substance P 21 , serving as chemo-sensitive nociceptors.…”

Section: Peripheral Dorsal Root Ganglion Neurons and Subclassesmentioning

confidence: 99%

A pharmacological and transcriptomic approach to exploring novel pain targets

Yin¹

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Ever since the discovery that mutations in the voltage-gated sodium channel 1.7 protein are responsible for human congenital insensitivity to pain, the voltage-gated sodium channel (Na V ) family of ion channels has been the subject of intense research with the hope of discovering novel analgesics. We now know that Na V 1.7 deletion in select neuronal populations yield different phenotypes, with the deletion of Na V 1.7 in all sensory neurons being successful at abolishing mechanical and heat-induced pain. However, it is rapidly becoming apparent that a number of pain syndromes are not modulated by Na V 1.7 at all, such as oxaliplatin-mediated neuropathy. It is particularly interesting to note that the loss of Na V 1.7 function is also associated with the selective inhibition of pain mediated by specific stimuli, such as that observed in burn-induced pain where Na V 1.7 gene knockout abolished thermal allodynia but did not affect mechanical allodynia. Accordingly, significant interests exist in delineating the contribution of other Na V isoforms in modality-specific pain pathways. Two other isoforms, Na V 1.6 and Na V 1.8, are now specifically implicated in some Na V 1.7-independent conditions such as oxaliplatin-induced cold allodynia. Such selective contributions of specific ion channel isoforms to pain highlight the need to discover other putative protein targets involved in mediating nociception.The aim of my work is therefore to discover selective molecular inhibitors of Na V 1.6 and Na V 1.8, to find useful cell models for peripheral nociceptors, to investigate the roles of Na V 1.6 and Na V 1.8 in an animal model of burn-induced pain, and to screen for putative new targets for analgesia in burn-related pain.Chapter 2 of this thesis describes activity-guided discovery of novel Na V 1.6 and Na V 1.8-modulting peptides from crude spider venoms. Crude venom from Poecilotheria metallica successfully reduced Na V 1.8-mediated voltage changes in HEK293-expressing cells. A new Na V 1.8-inhibitory peptide was sequenced from the venom and named Pme1a. However, Pme1a exhibited TRPV1 agonist activity and induced nocifensive behaviours, such as paw licking, after injection into the hind paws of mice, indicating the peptide was not a selective Na V 1.8 modulator and was unsuitable as a tool for Na V 1.8 investigation.iii With the unsuccessful exploration of spider venoms for new specific inhibitors, I then investigated in vitro cell models as tools to research specific nociceptor subtypes that express Na V 1.6 or Na V 1.8. In Chapter 3, I provide the first complete transcriptome of three common in vitro neuronal cell lines (SH-SY5Y, F-11, and ND7/23) to examine whether they were appropriate for investigating the functions of Na V 1.6 and Na V 1.8, and to identify if the cell lines resemble in vivo dorsal root ganglion (DRG) neuronal subclasses. The three cell lines examined all expressed proteins belonging to similar pathways and of similar proportions to native DRG neurons. However, they did not express any ce...

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Therapeutic opportunities for targeting cold pain pathways

Cited by 33 publications

References 185 publications

TRPM8 and TRPA1 do not contribute to dental pulp sensitivity to cold

TRPM8 and TRPA1 do not contribute to dental pulp sensitivity to cold

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

A pharmacological and transcriptomic approach to exploring novel pain targets

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