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Optical Assessment of Nociceptive TRP Channel Function at the Peripheral Nerve Terminal

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Optical Assessment of Nociceptive TRP Channel Function at the Peripheral Nerve Terminal International Journal of Molecular Sciences Review Optical Assessment of Nociceptive TRP Channel Function at the Peripheral Nerve Terminal Fernando Aleixandre-Carrera 1 , Nurit Engelmayer 2,3, David Ares-Suárez 1, María del Carmen Acosta 1 , Carlos Belmonte 1, Juana Gallar 1,4,Víctor Meseguer 1,*,† and Alexander M. Binshtok 2,3,† 1 Instituto de Neurociencias, Universidad Miguel Hernández—CSIC, 03550 San Juan de Alicante, Spain; [email protected] (F.A.-C.); [email protected] (D.A.-S.); [email protected] (M.d.C.A.); [email protected] (C.B.); [email protected] (J.G.) 2 Department of Medical Neurobiology, Institute for Medical Research Israel—Canada, Hadassah School of Medicine, The Hebrew University, Jerusalem 91123, Israel; [email protected] (N.E.); [email protected] (A.M.B.) 3 The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel 4 Instituto de Investigación Sanitaria y Biomédica de Alicante, 03550 San Juan de Alicante, Spain * Correspondence: [email protected] † Shared last authorship. Abstract: Free nerve endings are key structures in sensory transduction of noxious stimuli. In spite of this, little is known about their functional organization. Transient receptor potential (TRP) channels have emerged as key molecular identities in the sensory transduction of pain-producing stimuli, yet the vast majority of our knowledge about sensory TRP channel function is limited to data obtained from in vitro models which do not necessarily reflect physiological conditions. In recent years, the development of novel optical methods such as genetically encoded calcium indicators and photo-modulation of ion channel activity by pharmacological tools has provided an invaluable Citation: Aleixandre-Carrera, F.; opportunity to directly assess nociceptive TRP channel function at the nerve terminal. Engelmayer, N.; Ares-Suárez, D.; Acosta, M.d.C.; Belmonte, C.; Gallar, Keywords: peripheral nerve terminals; TRP channels; nociception; pain; optical recording; J.; Meseguer, V.; Binshtok, A.M. opto-pharmacology Optical Assessment of Nociceptive TRP Channel Function at the Peripheral Nerve Terminal. Int. J. Mol. Sci. 2021, 22, 481. https://doi.org/ 1. Introduction 10.3390/ijms22020481 In mammals, environmental information is predominantly relayed by peripheral Received: 21 December 2020 neurons of the somatosensory system. Such neurons are cellular sensors, transforming Accepted: 3 January 2021 mechanical, thermal, and chemical stimuli into electrical signals that progress to the central Published: 6 January 2021 nervous system (CNS) as action potentials [1]. Sensory neurons in mammals are pseudo- unipolar, possessing a single axon with two distinct branches: the peripheral branch which Publisher’s Note: MDPI stays neu- extends and innervates the target organs such as skin, viscera, and mucosae, and the central tral with regard to jurisdictional clai- branch which relays the collected information to second-order neurons of the CNS in the ms in published maps and institutio- spinal dorsal horn or brainstem sensory nuclei [2]. The cell bodies of primary sensory nal affiliations. neurons innervate the body group together in segmental order in dorsal root ganglia (DRGs), which are found lateral to the spinal cord (Figure1a). Primary sensory neuron cell bodies, which innervate the head and face, cluster in the trigeminal ganglia (TG) juxtaposed Copyright: © 2021 by the authors. Li- to the brain [3] (Figure1b). censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 481. https://doi.org/10.3390/ijms22020481 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 20 of pain immediately upon tissue damage [4], while C-nociceptors contribute to later stages Int. J. Mol. Sci. 2021, 22, 481 of chronic pain development, neurogenic inflammation, and sensitization [7]. 2 of 20 Figure 1. Schematic illustration depicting somatosensory innervation and their projections to the central nervous system (CNS).Figure ( 1.a)Schematic Somatosensory illustration nerve endings depicting innervatin somatosensoryg the skin innervation project to andthe dorsal their projections horn second-order to the central neurons nervous in the system spinal cord.(CNS). Three (a) Somatosensory functional types nerve of sensory endings neurons innervating innervating the skin projectthe skin to are the dorsalrepresen hornted second-orderalong with the neurons transient in the receptor spinal potentialcord. Three (TRP) functional channels types expressed. of sensory (b) Corneal neurons somatosensory innervating the nerve skin endings are represented densely alongpopulate with the the corneal transient epithelium, receptor reachpotential the (TRP)trigeminal channels ganglia expressed. (TG) through (b) Corneal the ophthalmic somatosensory nerve, nerve and endingsproject, together densely populatewith other the primary corneal nociceptive epithelium, neuronsreach the innervating trigeminal the ganglia face, (TG)to second-ord through theer CNS ophthalmic neurons nerve, at the andspinal project, part of together the trigeminal with other nuclei primary in the nociceptivebrainstem. Twoneurons functional innervating forms theof corneal face, to sens second-orderory neurons CNS and neurons the TRP at channels the spinal that part they of express the trigeminal are represented. nuclei in the brainstem. Two functional forms of corneal sensory neurons and the TRP channels that they express are represented. The ability of nociceptors to behave as noxious stimuli detectors relies on the pres- ence ofTraditionally, specialized sensorytransducing nerve molecules fibers have at beentheir classifiedperipheral into nerve four terminals types according capable of to transformingtheir conduction the velocitiesharmful physical [4]. Aα- and(thermal Aβ-fibers and mechanical) show highly and myelinated chemical axons stimuli and into fast generatorconduction potentials velocities, [4,8]. Aδ areUpon mildly nerve myelinated terminal stimulation, and have medium the output conduction signal conveying velocities, towhereas the CNS C-fibers depends lack on myelin the properties and have slowof tran conductionsducer channels velocities such [5]. as The transient sensory receptor neurons potentialsresponsible (TRPs), for detecting acid-sensing potentially ion channels harmful (ASICs), stimuli mostlyPiezo, and belong TACAN to the [9–15], C-fiber which or Aδ produceclass and generator are known potentials. as nociceptors Voltage-gated [6]. Aδ-nociceptors channels subsequently underlie the translate rapid component it into action of potentialpain immediately firing. TRP upon ion tissue channels damage are [among4], while the C-nociceptors most studied contribute transducer to laterchannels stages ex- of pressedchronic in pain nociceptors development, and play neurogenic a pivotal inflammation, role in the study and sensitizationof pain [4]. [7]. ToThe date, ability the ofmain nociceptors component to behaveof our knowl as noxiousedge on stimuli transducer detectors TRP relies channel on function the pres- atence the of nerve specialized terminal transducing has been inferred molecules from at theirexperimental peripheral data nerve obtained terminals from capable in vitro of transductiontransforming models the harmful lacking physical physiological (thermal condit andions mechanical) such as cell and lines chemical heterologously stimuli into ex- pressinggenerator TRP potentials channels [4, 8or]. cultured Upon nerve primary terminal sensory stimulation, neurons the [16]. output Although signal this conveying provided to invaluablethe CNS depends information on the on properties the roles ofTRP transducer channels channels play in nociception, such as transient the possible receptor altera- poten- tiontials of (TRPs), expression, acid-sensing distributi ionon, channels and modulation (ASICs), Piezo, by endogeno and TACANus factors [9–15 ],of which TRP channels produce generator potentials. Voltage-gated channels subsequently translate it into action potential firing. TRP ion channels are among the most studied transducer channels expressed in nociceptors and play a pivotal role in the study of pain [4]. Int. J. Mol. Sci. 2021, 22, 481 3 of 20 To date, the main component of our knowledge on transducer TRP channel function at the nerve terminal has been inferred from experimental data obtained from in vitro transduction models lacking physiological conditions such as cell lines heterologously expressing TRP channels or cultured primary sensory neurons [16]. Although this provided invaluable information on the roles TRP channels play in nociception, the possible alter- ation of expression, distribution, and modulation by endogenous factors of TRP channels under non-physiological conditions [17,18], and other factors such as distinct morphology between the nerve terminal and soma, might account for different coding of noxious stimuli by TRP channels in their physiological environment. Indeed, a recently published computa- tional model revealed that the structure of peripheral nociceptive terminal tree determines the output of the nociceptive neurons at the central terminal [19]. Since in vitro models do not recapitulate the entire nerve terminal complexity, there is an obvious need to assess TRP channel functionality
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