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Ion Channels of Nociception 2.0
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Ion Channels of Nociception 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 20769

Special Issue Editor

Prof. Dr. Rashid Giniatullin

E-Mail Website
Guest Editor
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, Neulaniementie 2, 70211 Kuopio, Finland
Interests: synaptic transmission; neuronal plasticity; neuron–glia interactions; neuronal networks; purinergic mechanisms; mechanosensitive ion channels; neurotransmitter receptors in health and disease; receptor desensitization; receptor trafficking; modelling of receptor kinetics; mitochondria; reactive oxygen species; molecular and cellular mechanisms of pain and analgesia; migraine; neuroprotection
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Molecular mechanisms of pain - especially of neuropathic, migraine and cancer pain - remain largely unsolved. It is known that pain signals are typically initiated in the peripheral terminals of dorsal root or trigeminal ganglia neurons. These nerve terminals are equipped with specific receptors reacting to chemical or physical stimuli, as well as a range of specific voltage-gated ion channels contributing to generation and propagation of nociceptive spikes.

The molecular structures of many ion channels implicated in nociception are known, facilitating the development of new anti-nociceptive (analgesic) medicines. However, some new players in nociception have emerged only recently, for example mechanosensitive Piezo and the CRAC Orai1 channels. Moreover, the function of some ion channels, especially those which can counteract nociception, for instance, potassium K2P channels, is not well characterized. There are also gaps in understanding the role of ion channels in situ, ion channel interactions, functional role of sensitization-desensitization and ion channel inactivation, endogenous modulators and other important aspects of functioning of excitable nociceptive neurons and partnering non-excitable cells.

This Special Issue on 'Ion Channels of Nociception' aims to collect reviews and original papers devoted to elucidating the role of receptor- and voltage-gated ion channels in pain signaling. Together, these will shed light on the molecular mechanisms underlying the generation and propagation of nociceptive signals, supporting research into new pain therapies.

Prof. Dr. Rashid Giniatullin
Guest Editor

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Keywords

  • pain
  • nociception
  • molecular mechanisms
  • molecular structures
  • migraine
  • neuropathic pain
  • cancer pain
  • nociceptive neurons
  • voltage-gated ion channels
  • ligand-gated ion channels
  • analgesic drugs
  • mechanosensitive Piezo channels
  • CRAC Orai1 channels
  • K2P channels
  • sodium channels
  • sensitization
  • ion channel inactivation

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Published Papers (7 papers)

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Research

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12 pages, 1645 KiB  
Article
Evaluation of the Ion Channel Assembly in a Eukaryotic Cell-Free System Focusing on Two-Pore Domain Potassium Channels K2P
by Jessica Ullrich, Carsten Ohlhoff, Srujan Kumar Dondapati, Anne Zemella and Stefan Kubick
Int. J. Mol. Sci. 2023, 24(7), 6299; https://doi.org/10.3390/ijms24076299 - 27 Mar 2023
Cited by 3 | Viewed by 2291
Abstract
Oligomeric ion channels are abundant in nature. However, the recombinant expression in cell culture-based systems remains tedious and challenging due to negative side effects, limiting the understanding of their role in health and disease. Accordingly, in this work, we demonstrate the cell-free synthesis [...] Read more.
Oligomeric ion channels are abundant in nature. However, the recombinant expression in cell culture-based systems remains tedious and challenging due to negative side effects, limiting the understanding of their role in health and disease. Accordingly, in this work, we demonstrate the cell-free synthesis (CFS) as an alternative platform to study the assembly of two-pore domain potassium channels (K2P) within endogenous endoplasmic reticulum-derived microsomes. Exploiting the open nature of CFS, we investigate the cotranslational translocation of TREK-2 into the microsomes and suggest a cotranslational assembly with typical single-channel behavior in planar lipid-bilayer electrophysiology. The heteromeric assembly of K2P channels is a contentious matter, accordingly we prove the successful assembly of TREK-2 with TWIK-1 using a biomolecular fluorescence complementation assay, Western blot analysis and autoradiography. The results demonstrate that TREK-2 homodimer assembly is the initial step, followed by heterodimer formation with the nascent TWIK-1, providing evidence of the intergroup heterodimerization of TREK-2 and TWIK-1 in eukaryotic CFS. Since K2P channels are involved in various pathophysiological conditions, including pain and nociception, CFS paves the way for in-depth functional studies and related pharmacological interventions. This study highlights the versatility of the eukaryotic CFS platform for investigating ion channel assembly in a native-like environment. Full article
(This article belongs to the Special Issue Ion Channels of Nociception 2.0)
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12 pages, 1675 KiB  
Communication
FM1-43 Dye Memorizes Piezo1 Activation in the Trigeminal Nociceptive System Implicated in Migraine Pain
by Adriana Della Pietra, Nikita Mikhailov and Rashid Giniatullin
Int. J. Mol. Sci. 2023, 24(2), 1688; https://doi.org/10.3390/ijms24021688 - 14 Jan 2023
Cited by 5 | Viewed by 2579
Abstract
It has been proposed that mechanosensitive Piezo1 channels trigger migraine pain in trigeminal nociceptive neurons, but the mechanosensitivity of satellite glial cells (SGCs) supporting neuronal sensitization has not been tested before. Moreover, tools to monitor previous Piezo1 activation are not available. Therefore, by [...] Read more.
It has been proposed that mechanosensitive Piezo1 channels trigger migraine pain in trigeminal nociceptive neurons, but the mechanosensitivity of satellite glial cells (SGCs) supporting neuronal sensitization has not been tested before. Moreover, tools to monitor previous Piezo1 activation are not available. Therefore, by using live calcium imaging with Fluo-4 AM and labeling with FM1-43 dye, we explored a new strategy to identify Piezo channels’ activity in mouse trigeminal neurons, SGCs, and isolated meninges. The specific Piezo1 agonist Yoda1 induced calcium transients in both neurons and SGCs, suggesting the functional expression of Piezo1 channels in both types of cells. In Piezo1-transfected HEK cells, FM1-43 produced only a transient fluorescent response, whereas co-application with Yoda1 provided higher transient signals and a remarkable long-lasting FM1-43 ‘tail response’. A similar Piezo1-related FM1-43 trapping was observed in neurons and SGCs. The non-specific Piezo channel blocker, Gadolinium, inhibited the transient peak, confirming the involvement of Piezo1 receptors. Finally, FM1-43 labeling demonstrated previous activity in meningeal tissues 3.5 h after Yoda1 washout. Our data indicated that trigeminal neurons and SGCs express functional Piezo channels, and their activation provides sustained labeling with FM1-43. This long-lasting labelling can be used to monitor the ongoing and previous activation of Piezo1 channels in the trigeminal nociceptive system, which is implicated in migraine pain. Full article
(This article belongs to the Special Issue Ion Channels of Nociception 2.0)
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15 pages, 1807 KiB  
Article
Analgesic Action of Acetaminophen via Kv7 Channels
by Jan-Luca Stampf, Cosmin I. Ciotu, Stefan Heber, Stefan Boehm, Michael J. M. Fischer and Isabella Salzer
Int. J. Mol. Sci. 2023, 24(1), 650; https://doi.org/10.3390/ijms24010650 - 30 Dec 2022
Cited by 1 | Viewed by 1931
Abstract
The mechanism of acetaminophen (APAP) analgesia is at least partially unknown. Previously, we showed that the APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI) activated Kv7 channels in neurons in vitro, and this activation of Kv7 channels dampened neuronal firing. Here, the effect of the Kv7 [...] Read more.
The mechanism of acetaminophen (APAP) analgesia is at least partially unknown. Previously, we showed that the APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI) activated Kv7 channels in neurons in vitro, and this activation of Kv7 channels dampened neuronal firing. Here, the effect of the Kv7 channel blocker XE991 on APAP-induced analgesia was investigated in vivo. APAP had no effect on naive animals. Induction of inflammation with λ-carrageenan lowered mechanical and thermal thresholds. Systemic treatment with APAP reduced mechanical hyperalgesia, and co-application of XE991 reduced APAP’s analgesic effect on mechanical pain. In a second experiment, the analgesic effect of systemic APAP was not antagonized by intrathecal XE991 application. Analysis of liver samples revealed APAP and glutathione-coupled APAP indicative of metabolization. However, there were no relevant levels of these metabolites in cerebrospinal fluid, suggesting no relevant APAP metabolite formation in the CNS. In summary, the results support an analgesic action of APAP by activating Kv7 channels at a peripheral site through formation of the metabolite NAPQI. Full article
(This article belongs to the Special Issue Ion Channels of Nociception 2.0)
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14 pages, 1742 KiB  
Article
Activation of Meningeal Afferents Relevant to Trigeminal Headache Pain after Photothrombotic Stroke Lesion: A Pilot Study in Mice
by Georgii Krivoshein, Abdulhameed Bakreen, Arn M. J. M. van den Maagdenberg, Tarja Malm, Rashid Giniatullin and Jukka Jolkkonen
Int. J. Mol. Sci. 2022, 23(20), 12590; https://doi.org/10.3390/ijms232012590 - 20 Oct 2022
Cited by 4 | Viewed by 2300
Abstract
Stroke can be followed by immediate severe headaches. As headaches are initiated by the activation of trigeminal meningeal afferents, we assessed changes in the activity of meningeal afferents in mice subjected to cortical photothrombosis. Cortical photothrombosis induced ipsilateral lesions of variable sizes that [...] Read more.
Stroke can be followed by immediate severe headaches. As headaches are initiated by the activation of trigeminal meningeal afferents, we assessed changes in the activity of meningeal afferents in mice subjected to cortical photothrombosis. Cortical photothrombosis induced ipsilateral lesions of variable sizes that were associated with contralateral sensorimotor impairment. Nociceptive firing of mechanosensitive Piezo1 channels, activated by the agonist Yoda1, was increased in meningeal afferents in the ischemic hemispheres. These meningeal afferents also had a higher maximal spike frequency at baseline and during activation of the mechanosensitive Piezo1 channel by Yoda1. Moreover, in these meningeal afferents, nociceptive firing was active during the entire induction of transient receptor potential vanilloid 1 (TRPV1) channels by capsaicin. No such activation was observed on the contralateral hemi-skulls of the same group of mice or in control mice. Our data suggest the involvement of mechanosensitive Piezo1 channels capable of maintaining high-frequency spiking activity and of nociceptive TRPV1 channels in trigeminal headache pain responses after experimental ischemic stroke in mice. Full article
(This article belongs to the Special Issue Ion Channels of Nociception 2.0)
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16 pages, 3298 KiB  
Article
Spinal TRPA1 Contributes to the Mechanical Hypersensitivity Effect Induced by Netrin-1
by Hong Wei, Liisa Ailanen, Miguel Morales, Ari Koivisto and Antti Pertovaara
Int. J. Mol. Sci. 2022, 23(12), 6629; https://doi.org/10.3390/ijms23126629 - 14 Jun 2022
Cited by 3 | Viewed by 2186
Abstract
Netrin-1, a chemoattractant expressed by floor plate cells, and one of its receptors (deleted in colorectal cancer) has been associated with pronociceptive actions in a number of pain conditions. Here, we addressed the question of whether spinal TRPC4/C5 or TRPA1 are among the [...] Read more.
Netrin-1, a chemoattractant expressed by floor plate cells, and one of its receptors (deleted in colorectal cancer) has been associated with pronociceptive actions in a number of pain conditions. Here, we addressed the question of whether spinal TRPC4/C5 or TRPA1 are among the downstream receptors contributing to pronociceptive actions induced by netrin-1. The experiments were performed on rats using a chronic intrathecal catheter for administration of netrin-1 and antagonists of TRPC4/C5 or TRPA1. Pain sensitivity was assessed behaviorally by using mechanical and heat stimuli. Effect on the discharge rate of rostral ventromedial medullary (RVM) pain control neurons was studied in lightly anesthetized animals. Netrin-1, in a dose-related fashion, induced mechanical hypersensitivity that lasted up to three weeks. Netrin-1 had no effect on heat nociception. Mechanical hypersensitivity induced by netrin-1 was attenuated by TRPA1 antagonist Chembridge-5861528 and by the control analgesic compound pregabalin both during the early (first two days) and late (third week) phase of hypersensitivity. TRPC4/C5 antagonist ML-204 had a weak antihypersensitivity effect that was only in the early phase, whereas TRPC4/C5 antagonist HC-070 had no effect on hypersensitivity induced by netrin-1. The discharge rate in pronociceptive ON-like RVM neurons was increased by netrin-1 during the late but not acute phase, whereas netrin-1 had no effect on the discharge rate of antinociceptive RVM OFF-like neurons. The results suggest that spinal TRPA1 receptors and pronociceptive RVM ON-like neurons are involved in the maintenance of submodality-selective pronociceptive actions induced by netrin-1 in the spinal cord. Full article
(This article belongs to the Special Issue Ion Channels of Nociception 2.0)
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Review

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26 pages, 3289 KiB  
Review
The Yin/Yang Balance of Communication between Sensory Neurons and Macrophages in Traumatic Peripheral Neuropathic Pain
by Roxana-Olimpia Gheorghe, Andreea Violeta Grosu, Melania Bica-Popi and Violeta Ristoiu
Int. J. Mol. Sci. 2022, 23(20), 12389; https://doi.org/10.3390/ijms232012389 - 16 Oct 2022
Cited by 6 | Viewed by 5216
Abstract
Traumatic peripheral neuropathic pain is a complex syndrome caused by a primary lesion or dysfunction of the peripheral nervous system. Secondary to the lesion, resident or infiltrating macrophages proliferate and initiate a cross-talk with the sensory neurons, at the level of peripheral nerves [...] Read more.
Traumatic peripheral neuropathic pain is a complex syndrome caused by a primary lesion or dysfunction of the peripheral nervous system. Secondary to the lesion, resident or infiltrating macrophages proliferate and initiate a cross-talk with the sensory neurons, at the level of peripheral nerves and sensory ganglia. The neuron–macrophage interaction, which starts very early after the lesion, is very important for promoting pain development and for initiating changes that will facilitate the chronicization of pain, but it also has the potential to facilitate the resolution of injury-induced changes and, consequently, promote the reduction of pain. This review is an overview of the unique characteristics of nerve-associated macrophages in the peripheral nerves and sensory ganglia and of the molecules and signaling pathways involved in the neuro-immune cross-talk after a traumatic lesion, with the final aim of better understanding how the balance between pro- and anti-nociceptive dialogue between neurons and macrophages may be modulated for new therapeutic approaches. Full article
(This article belongs to the Special Issue Ion Channels of Nociception 2.0)
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19 pages, 3333 KiB  
Review
Inhibiting Endocannabinoid Hydrolysis as Emerging Analgesic Strategy Targeting a Spectrum of Ion Channels Implicated in Migraine Pain
by Adriana Della Pietra, Juha Savinainen and Rashid Giniatullin
Int. J. Mol. Sci. 2022, 23(8), 4407; https://doi.org/10.3390/ijms23084407 - 15 Apr 2022
Cited by 7 | Viewed by 3279
Abstract
Migraine is a disabling neurovascular disorder characterized by severe pain with still limited efficient treatments. Endocannabinoids, the endogenous painkillers, emerged, alternative to plant cannabis, as promising analgesics against migraine pain. In this thematic review, we discuss how inhibition of the main endocannabinoid-degrading enzymes, [...] Read more.
Migraine is a disabling neurovascular disorder characterized by severe pain with still limited efficient treatments. Endocannabinoids, the endogenous painkillers, emerged, alternative to plant cannabis, as promising analgesics against migraine pain. In this thematic review, we discuss how inhibition of the main endocannabinoid-degrading enzymes, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), could raise the level of endocannabinoids (endoCBs) such as 2-AG and anandamide in order to alleviate migraine pain. We describe here: (i) migraine pain signaling pathways, which could serve as specific targets for antinociception; (ii) a divergent distribution of MAGL and FAAH activities in the key regions of the PNS and CNS implicated in migraine pain signaling; (iii) a complexity of anti-nociceptive effects of endoCBs mediated by cannabinoid receptors and through a direct modulation of ion channels in nociceptive neurons; and (iv) the spectrum of emerging potent MAGL and FAAH inhibitors which efficiently increase endoCBs levels. The specific distribution and homeostasis of endoCBs in the main regions of the nociceptive system and their generation ‘on demand’, along with recent availability of MAGL and FAAH inhibitors suggest new perspectives for endoCBs-mediated analgesia in migraine pain. Full article
(This article belongs to the Special Issue Ion Channels of Nociception 2.0)
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