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Ion Channels of Nociception International Journal of Molecular Sciences Editorial Ion Channels of Nociception Rashid Giniatullin A.I. Virtanen Institute, University of Eastern Finland, 70211 Kuopio, Finland; Rashid.Giniatullin@uef.fi; Tel.: +358-403553665 Received: 13 May 2020; Accepted: 15 May 2020; Published: 18 May 2020 Abstract: The special issue “Ion Channels of Nociception” contains 13 articles published by 73 authors from different countries united by the main focusing on the peripheral mechanisms of pain. The content covers the mechanisms of neuropathic, inflammatory, and dental pain as well as pain in migraine and diabetes, nociceptive roles of P2X3, ASIC, Piezo and TRP channels, pain control through GPCRs and pharmacological agents and non-pharmacological treatment with electroacupuncture. Keywords: pain; nociception; sensory neurons; ion channels; P2X3; TRPV1; TRPA1; ASIC; Piezo channels; migraine; tooth pain Sensation of pain is one of the fundamental attributes of most species, including humans. Physiological (acute) pain protects our physical and mental health from harmful stimuli, whereas chronic and pathological pain are debilitating and contribute to the disease state. Despite active studies for decades, molecular mechanisms of pain—especially of pathological pain—remain largely unaddressed, as evidenced by the growing number of patients with chronic forms of pain. There are, however, some very promising advances emerging. A new field of pain treatment via neuromodulation is quickly growing, as well as novel mechanistic explanations unleashing the efficiency of traditional techniques of Chinese medicine. New molecular actors with important roles in pain mechanisms are being characterized, such as the mechanosensitive Piezo ion channels [1]. Pain signals are detected by specialized sensory neurons, emitting nerve impulses encoding pain in response to noxious stimuli. Many of these nociceptive neurons are equipped with a rich repertoire of specific ion channels which serve as pain transducers. These ion channels are located at the peripheral terminals of dorsal root or trigeminal ganglia neurons as well as in sensory neurons of the viscera (Figure1). Pain transducers react to a variety of chemical or physical stimuli (algogens) by opening the ion channels and inducing neuronal depolarization known as the generator potential. These pain transducers include ATP-gated P2X3, classical heat/capsaicin-sensitive TRPV1 and cold/redox-sensitive TRPA1 channels, acid sensitive ion channels (ASICs), and mechanosensitive Piezo, to name just a few (Figure1, for further details see the classical review [ 2]). Sufficiently high generator potential, assisted by voltage-gated sodium channels, initiates the propagating action potentials (spikes). Some voltage-gated channels are expressed exclusively in nociceptive neurons, for instance, sodium Nav1.8 and Nav1.9 channels [3]. The peripheral pain signals travel via the multi-synaptic network of the nociceptive system to the higher pain centers to be perceived as a feeling of pain. A remarkable property of nociceptive neurons is sensitisation (enhanced responsiveness to triggers of pain). This phenomenon, a type of neuronal plasticity, can be mediated by a plethora of metabotropic receptors for different classes of pain modulators: classical mediators, neurotrophins, cytokines, and other active molecules (Figure1). Normally, many pain transducers are in “sleeping” or low activity mode, but they can become very active during the action of these endogenous modulators triggering neuronal sensitization. The fundamental approach: “treat pain at the source” provides a strategic rationale to diminish pain by counteracting its peripheral mechanisms. The knowledge of the function and structure of Int. J. Mol. Sci. 2020, 21, 3553; doi:10.3390/ijms21103553 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 3553 2 of 6 pain transducers and associated ion channels is essential to develop new medicines. The fact that the molecular structures of most ion channels implicated in nociception are known facilitates the development of new anti-nociceptive (analgesic) medicines. Direct targeting of pain transducers by specific blockers provides an opportunity to block pain mediated by these ion channels. However, this is a challenging task since the lifetime of channels on the membrane is limited because of the continuous traffic and renewal as it was shown for the nociceptive P2X3 receptors [4]. FigureFigure 1.1. ChemicalChemical andand physicalphysical stimulistimuli (algogens)(algogens) activatingactivating ionion channelchannel ofof nociceptionnociception andand painpain modulatorsmodulators actingacting atat thethe nervenerve terminal terminal of of the the nociceptive nociceptive neuron. neuron. TheThe nervenerve terminalterminal expressesexpresses specificspecific ionion channelschannels ofof nociceptionnociception suchsuch asas ATP-gatedATP-gated P2X3, P2X3, heat heat/capsaicin-sensitive/capsaicin-sensitive TRPV1TRPV1 andand coldcold/redox-sensitive/redox-sensitive TRPA1 TRPA1 channels, channels, acid-sensitive acid-sensiti ionve channelsion channels (ASICs) (ASICs and) mechanosensitive and mechanosensitive Piezo channels.Piezo channels. The activity The ofactivity these painof these transducers pain transducers can be enhanced can be leading enhanced to the leading neuronal to sensitization,the neuronal viasensitization, metabotropic via receptors, metabotropic by different receptors, classes ofby pain different modulators classes including of pain neuropeptides, modulators hormones,including classicalneuropeptides, mediators, hormones, neurotrophins, classical cytokines, mediators, and neurotrophins, other endogenous cytokines, pro-nociceptive and other endogenous molecules. pro- nociceptive molecules. This special issue “Ion Channels of Nociception” contains 13 articles published by 73 authors from differentA remarkable countries united property by theof mainnociceptive focusing neurons on the peripheralis sensitisation mechanisms (enhanced of pain.responsiveness The content to coverstriggers the of mechanisms pain). This phenomenon, of neuropathic, a inflammatory,type of neuronal and plasticity, dental pain can as be well mediated as pain inby migraine a plethora and of diabetes,metabotropic nociceptive receptors roles for of different P2X3, ASIC, classes Piezo of pain and TRPmodulators: channels, classical pain control mediators, through neurotrophins, GPCRs and pharmacologicalcytokines, and other agents active and molecules non-pharmacological (Figure 1). Normally, treatment many with electroacupuncture. pain transducers are in “sleeping” or lowNot activity surprisingly, mode, the but majority they can of become papers invery this active collection during are the devoted action toof thethese functioning endogenous of TRPmodulators channels, triggering which are ne theuronal best-studied sensitization. transducers of noxious stimuli but still a puzzling issue for theThe researchers. fundamental In approach: the large “treat family pain of TRP at the channels, source” provides TRPV1 and a strategic TRPA1 rationale are best knownto diminish for theirpain leadingby counteracting role in key its pain peripheral mechanisms. mechanisms. TRPV1 receptorsThe knowledge are often of the co-expressed function and with structure TRPA1 inof nociceptivepain transducers neurons and and associated probably ion can channels interact byis essential means of to the develop protein new TMEM100. medicines. The The details fact ofthat such the interactionsmolecular structures are discussed of inmost the well-illustratedion channels implicated review by Takayamain nociception and co-workers are known [5] summarizingfacilitates the thedevelopment role TRP channels of new playanti-nociceptive in the pain states(analgesic) including medicines. acute pain, Direct inflammatory targeting of pain,pain migrainetransducers pain, by andspecific other blockers disorders. provides Much attentionan opportunity in this to review block is pain paid mediated to the ANO1 by these protein, ion achannels. calcium-activated However, chloridethis is achannel challenging expressed task since in nociceptive the lifetime neurons. of channels The authors on the propose membrane that TRPis limited channels because and ANO1 of the cancontinuous collaborate traffic to generateand renewal a strong as it was pain sh signalown for in primarythe nociceptive sensory P2X3 neurons. receptors This [4]. is an interesting “marriage”This special between issue cation “Ion and Channels anion permeable of Nociception” ion channels contains to control13 articles the neuronalpublished excitability. by 73 authors fromBy different focusing countries on TRPA1 united channels, by Fengthe main and colleagues focusing [on6], usingthe peripheral electrophysiological mechanisms recordings of pain. from The brainstemcontent covers slices, the detected mechanisms activation of ofneuropathic, presynaptic inflammatory, polymodal TRPA1 and dental ion channels pain as in well glutamatergic as pain in terminalsmigraine synapsingand diabetes, on nociceptive the caudal nucleus roles of ofP2X3, the solitaryASIC, Piezo tract and neurons. TRP channels, The enhanced pain control glutamatergic through GPCRs and pharmacological agents and non-pharmacological treatment with electroacupuncture. Not surprisingly, the majority of papers in this collection are devoted to the functioning of TRP channels, which are the best-studied transducers of noxious stimuli but still a puzzling issue for the researchers. In the large
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