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Presynaptic Inhibition of Pain and Touch in the Spinal Cord: from Receptors to Circuits

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Presynaptic Inhibition of Pain and Touch in the Spinal Cord: from Receptors to Circuits International Journal of Molecular Sciences Review Presynaptic Inhibition of Pain and Touch in the Spinal Cord: From Receptors to Circuits Antonella Comitato and Rita Bardoni * Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-059-205-5227 Abstract: Sensory primary afferent fibers, conveying touch, pain, itch, and proprioception, synapse onto spinal cord dorsal horn neurons. Primary afferent central terminals express a wide variety of receptors that modulate glutamate and peptide release. Regulation of the amount and timing of neurotransmitter release critically affects the integration of postsynaptic responses and the coding of sensory information. The role of GABA (γ-aminobutyric acid) receptors expressed on afferent central terminals is particularly important in sensory processing, both in physiological conditions and in sensitized states induced by chronic pain. During the last decade, techniques of opto- and chemogenetic stimulation and neuronal selective labeling have provided interesting insights on this topic. This review focused on the recent advances about the modulatory effects of presynaptic GABAergic receptors in spinal cord dorsal horn and the neural circuits involved in these mechanisms. Keywords: sensory transmission; dorsal horn; presynaptic inhibition; GABA 1. Introduction The spinal cord dorsal horn represents the principal station where primary afferent fibers (PAFs) terminate, carrying information about several somatic sensory modalities. Citation: Comitato, A.; Bardoni, R. Presynaptic Inhibition of Pain and Primary afferent fibers transmitting pain, touch, itch, and proprioceptive inputs project Touch in the Spinal Cord: From to different dorsal horn laminae (laminae I–VI) (Figure1), synapsing onto excitatory and Receptors to Circuits. Int. J. Mol. Sci. inhibitory interneurons and projection neurons. PAFs belong to different categories (Aα, 2021, 22, 414. https://doi.org/ Aβ,Aδ, and C) that convey distinct sensory modalities. In particular, the fiber groups 10.3390/ijms22010414 relevant to this review include: (1) myelinated Aβ and low threshold (LT) Aδ fibers, mediating innocuous mechanical sensitivity, and mainly projecting to lamina II inner, III, Received: 24 November 2020 and IV; (2) high threshold (HT) myelinated Aδ and unmyelinated C fibers, mediating pain, Accepted: 30 December 2020 thermal sensations, and itch, and mainly terminating in lamina I and II. Some nociceptive Published: 2 January 2021 and tactile inputs also reach lamina V, where they converge on wide dynamic range neurons. Muscle afferent fibers were not considered in this review. Publisher’s Note: MDPI stays neu- The variety of neurons in the spinal cord makes the investigation of dorsal horn tral with regard to jurisdictional clai- circuits difficult. Based on the expression of distinct neurochemical markers, several classes ms in published maps and institutio- of neurons have been identified in rodent lamina I, II, and III of the dorsal horn, exhibit- nal affiliations. ing different morphologies and functional properties [1–4]. The transgenic expression of fluorescent proteins, such as EGFP or tdTomato, driven by a cell-type-specific promoter, has allowed the characterization of morphological and electrophysiological properties of Copyright: © 2021 by the authors. Li- specific neuron populations. Glutamatergic excitatory interneurons, involved in pain and censee MDPI, Basel, Switzerland. touch transmission, include neurons expressing somatostatin (SOM+), cholecystokinin This article is an open access article (CCK+), calretinin (CR+), protein kinase C gamma (PKCγ+), and vesicular glutamate distributed under the terms and con- transporter 3 (vGlut3+). GABAergic and glycinergic inhibitory interneurons include neu- ditions of the Creative Commons At- rons expressing parvalbumin (PV+), dynorphin (DYN+), galanin (partially overlapping tribution (CC BY) license (https:// with DYN+), neuronal nitric oxide synthase (nNOS+), and early expressed tyrosin kinase creativecommons.org/licenses/by/ receptor RET (early RET+, partially overlapping with PV+). Nociceptive projection neurons 4.0/). Int. J. Mol. Sci. 2021, 22, 414. https://doi.org/10.3390/ijms22010414 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 13 Int. J. Mol. Sci. 2021, 22, 414 2 of 13 receptor RET (early RET+, partially overlapping with PV+). Nociceptive projection neu- are mostly located in lamina I and relay sensory information to the brain stem and the rons are mostly located in lamina I and relay sensory information to the brain stem and thalamus. A subpopulation of these neurons expresses the neurokinin receptor NK1. the thalamus. A subpopulation of these neurons expresses the neurokinin receptor NK1. Figure 1. Organization of primary afferent fibers projecting to spinal cord dorsal horn. Nociceptive Figure 1. Organization of primary afferent fibers projecting to spinal cord dorsal horn. Nociceptive fibers terminate mainly in superficial dorsal horn (laminae I–II), while tactile afferents (Aβ and LT fibers terminate mainly in superficial dorsal horn (laminae I–II), while tactile afferents (Aβ and (low threshold) Aδ) project mainly to deep dorsal horn (laminae III–V). Nociceptive projection δ LTneurons (low threshold) are located A in) projectlamina mainlyI (black tocircles), deep dorsalwhile wide horn dynamic (laminae range III–V). neurons Nociceptive (orange projection circles), neuronsactivated are by located both tactile in lamina and nociceptive I (black circles), stimuli, while are wide localized dynamic in lamina range V. neurons Muscle (orange afferent circles), fibers activated(Aα) are bynotboth considered tactile andin this nociceptive diagram. stimuli, are localized in lamina V. Muscle afferent fibers (Aα) are not considered in this diagram. Primary afferent terminals release primarily glutamate onto dorsal horn neurons. A subclassPrimary of A afferentδ and Cterminals fibers also release contains primarily peptides, glutamate such as ontoSubstance dorsal P hornor CGRP, neurons. and/or A subclassneurotrophic of Aδ factorsand C fibers(BDNF, also GDNF). contains peptides, such as Substance P or CGRP, and/or neurotrophicThe “first factors synapse” (BDNF, in dorsal GDNF). horn represents the first opportunity to modify sensory informationThe “first entering synapse” the in spinal dorsal cord horn and represents it is subjected the first to opportunitya very complex to modify and fine sensory modu- informationlation. Numerous entering ion the channels spinal cord and andligand-gated it is subjected receptors to a very are involved complex in and the fine modulation modula- tion.of glutamate Numerous and ion peptide channels rele andase ligand-gated from PAFs, thereby receptors contro are involvedlling the in impact the modulation of sensory of glutamate and peptide release from PAFs, thereby controlling the impact of sensory input on second order neurons. In this review, we will present some recent studies about input on second order neurons. In this review, we will present some recent studies about GABA-mediated presynaptic modulation at the first synapse in spinal cord dorsal horn, GABA-mediated presynaptic modulation at the first synapse in spinal cord dorsal horn, focusing on the neural circuits involved. focusing on the neural circuits involved. 2.2. GABAergicGABAergic Inhibition Inhibition on on Primary Primary Afferent Afferent Fibers Fibers GABAergicGABAergic interneurons interneurons play play a a critical critical role role in in regulating regulating nociceptive nociceptive signal signal strength strength andand separating separating nociception nociception from from touch. touch. IntrathecalIntrathecal applicationapplication ofof bicucullinebicuculline andand strych-strych- nine (antagonists of GABAA and glycine receptors, respectively) increases responses nine (antagonists of GABAA and glycine receptors, respectively) increases responses evokedevoked byby exposure to noxious noxious stimuli stimuli [5]. [5]. According According to the to the gate gate theory theory of pain, of pain, proposed pro- posedby Melzack by Melzack and Wall and Wall[6], stimulation [6], stimulation of A ofβ fibers Aβ fibers activate activate inhibito inhibitoryry interneurons interneurons in the in thedorsal dorsal horn, horn, “closing “closing the the gate” gate” to to nociceptiv nociceptivee transmission. transmission. ConditionsConditions ofof disinhibitiondisinhibition (either(either pharmacological pharmacological oror induced induced by by persistent persistent pain) pain) “open “open the the gate”, gate”, increasing increasing pain pain responseresponse and and causing causing allodynia allodynia (i.e., (i.e., the the perception perception of of an an innocuous innocuous stimulus stimulus as as noxious). noxious). PresynapticPresynaptic GABAGABA receptorsreceptors locatedlocated onon PAFPAF terminals terminals are are involved involved in in gating gating both both tactiletactile and and noxious noxious stimuli stimuli in in the the dorsal dorsal horn. horn. Indeed, Indeed, GABA GABA receptors receptors of of the the A A and and B B type type areare expressed expressed on on both both nociceptive nociceptive and and non-nociceptive non-nociceptive PAFs, PAFs, where where axo-axonic axo-axonic synapses synapses havehave been been described. described. GABAGABAAAreceptors receptors(GABA (GABAAARs)Rs) areare ligand-gatedligand-gated
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