Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 14(632)

Published: Feb. 16, 2022

Nociceptors are specialized sensory neurons that detect damaging or potentially stimuli and found in the dorsal root ganglia (DRG) trigeminal ganglia. These critical for generation of neuronal signals ultimately create perception pain. also primary targets treating acute chronic Single-cell transcriptomics on mouse nociceptors has transformed our understanding pain mechanisms. We sought to generate equivalent information human with goal identifying transcriptomic signatures nociceptors, species differences potential drug targets. used spatial molecularly characterize transcriptomes single DRG from eight organ donors. identified 12 clusters neurons, 5 which C as well 1 low-threshold mechanoreceptors (LTMRs), Aβ nociceptor, 2 Aδ, Aβ, proprioceptor subtypes. By focusing expression profiles ion channels, G protein-coupled receptors (GPCRs), other pharmacological targets, we provided a rich map direct comparison neuron transcriptomes. compared subtypes nonhuman primates showing conserved patterns gene among many cell types but divergence specific nociceptor subsets. Last, sex subpopulation transcriptomes, including marked increase calcitonin-related polypeptide alpha (CALCA) female pruritogen receptor-enriched nociceptors. This comprehensive characterization might open door development better treatments disorders.

Language: Английский

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Innovations and advances in modelling and measuring pain in animals

Nature reviews. Neuroscience, Journal Year: 2021, Volume and Issue: 23(2), P. 70 - 85

Published: Nov. 26, 2021

Language: Английский

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RNA profiling of human dorsal root ganglia reveals sex differences in mechanisms promoting neuropathic pain

Brain, Journal Year: 2022, Volume and Issue: 146(2), P. 749 - 766

Published: July 22, 2022

Neuropathic pain is a leading cause of high-impact pain, often disabling and poorly managed by current therapeutics. Here we focused on unique group neuropathic patients undergoing thoracic vertebrectomy where the dorsal root ganglia removed as part surgery allowing for molecular characterization identification mechanistic drivers independently preclinical models. Our goal was to quantify whole transcriptome RNA abundances using RNA-seq in pain-associated human from these patients, comprehensive changes samples contrasting them with non-pain-associated ganglia. We sequenced 70 ganglia, among 50 met inclusion criteria sufficient neuronal mRNA signal downstream analysis. expression analysis revealed profound sex differences differentially expressed genes including increase IL1B, TNF, CXCL14 OSM male CCL1, CCL21, PENK TLR3 female associated pain. Coexpression modules enrichment members JUN-FOS signalling males centromere protein coding females. Neuro-immune pathways distinct cytokine (OSM, LIF, SOCS1) females (CCL1, CCL19, CCL21). validated cellular profiles subset findings RNAscope situ hybridization. give direct support underlying mechanisms patient populations.

Language: Английский

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New perspectives in diabetic neuropathy

Neuron, Journal Year: 2023, Volume and Issue: 111(17), P. 2623 - 2641

Published: May 31, 2023

Language: Английский

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A role for proprioceptors in sngception

Science Advances, Journal Year: 2025, Volume and Issue: 11(5)

Published: Jan. 31, 2025

Proprioceptors are primary mechanosensory neurons to monitor the status of muscle contraction and/or body position ( 1 ). Although proprioceptors known as non-nociceptive mechanoreceptors, they also express pro-nociceptive acid-sensing ion channel 3 (ASIC3) 2 – 5 To probe role for in sensing acidosis (or sngception) 6 ), we found that genetic deletion Asic3 but not nociceptors abolished acid-induced chronic hyperalgesia mice. Chemo-optogenetically activating resulted hyperalgesic priming favored pain induced by acidosis. In humans, intramuscular acidification acid perception pain. Conversely, a spinal cord–injured patient who lost sensation right leg, proprioception and sngception were remaining somatosensory functions, associated with dorsal column. Together, evidence from both mouse human studies suggests sngception.

Language: Английский

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Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

Frontiers in Pain Research, Journal Year: 2021, Volume and Issue: 2

Published: Dec. 13, 2021

The persistence of increased excitability and spontaneous activity in injured peripheral neurons is imperative for the development many forms neuropathic pain. This aberrant involves and/or expression voltage-gated Na

Language: Английский

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Persistent nociceptor hyperactivity as a painful evolutionary adaptation

Trends in Neurosciences, Journal Year: 2023, Volume and Issue: 46(3), P. 211 - 227

Published: Jan. 5, 2023

Language: Английский

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Molecular taxonomy of nociceptors and pruriceptors

Pain, Journal Year: 2023, Volume and Issue: 164(6), P. 1245 - 1257

Published: Jan. 25, 2023

1. Introduction The ability to feel the warmth of sun or coolness a breeze on summer's day; pleasant caress skin; explore texture, size, and shape an object; pain as mechanism protect us from what is dangerous around has fascinated mankind for centuries. Perhaps this fascination rooted in fact that somatic senses temperature, pain, touch, itch, proprioception endow with continuously stay contact world within us. Attempting explain how we react heat, 17th century philosopher René Descartes depicted thread connecting skin brain particles fire pulling thread.20 In 1880s, distinct sensory spots were recognized shown respond specific stimuli, such cold. This finding was taken evidence different sensations relying existence nerves tuned types stimuli.83,94 beginning 20th century, discovery nerve fiber conduction velocities, activation thresholds, refractory periods made it possible link unique qualities sensation, kinds touch. Unlike innocuous touch pressure, which are communicated through fibers responding only mechanical noxious stimuli found activate class polymodal nociceptive several unpleasant including high-threshold force intense heat.7,12 work led general idea capacity discriminate perceptual arises functions variety neurons involved sensation. because neuron transduce certain, but not all, warm cool temperatures, cold, light punctate painful sharp objects, hair pull, chemical irritants, inflammatory substances, various vibration.29,38 Apart providing awareness about our body its surroundings, somatosensory system also essential other perform effortlessly without much thought. For example, continuous flow information sensory–motor feedback loop involving dozen muscles necessary coordinate movements when taking sip glass water seemingly simple task walking. Somatosensory organized discreet pathways autonomic sympathetic parasympathetic motor driving reflexes physiological homeostasis, thermoregulation reflex control sweat glands selective vasoconstrictor systems muscle active standing up during hypothermia, respectively.16,49,74 Furthermore, involve discriminative perception coordination efferent emotional motivational components important behavior. social hugging caressing induce pleasantness facilitate bonding, affiliative behavior, well-being,82,88 while convey protective include affective-motivational dimension unpleasantness contributing long-term behavior avoiding harm.112,125 molecularly coding each quality somatosensation unlikely. Instead, summation activity inactivity likely contribute dimensions involved. Several recent studies support conjecture, eg. sensation simultaneous warmth-sensing inhibition cold-sensing nerves97; requirement affective coping elicited by same stimuli45; suppression cold (−10 10°C) Calca+ neurons18,81; modulation touch-evoked itch Merkel cells Slc17a8-lineage (low-threshold mechanoreceptor [LTMR]) neurons32,33,108; alleviation Npy2r+ neuron-dependent acute A-LTMR neurons.3 With thorough molecular categorization types, experiments can be designed even greater precision, opening possibilities gaining new, deeper insights into cellular basis nociception pruriception. 2. Categorizing Sensory have historically been classified based properties, morphology, target innervation, spinal termination, developmental hierarchy, functional neurochemical properties (reviewed Emery Ernfors, 202029). instrumental deciphering peripheral nervous organized. However, these strategies measured so quantitative features, response stimuli; velocity; size; handful marker genes, might sufficient reliable identification units. By contrast, single-cell RNA sequencing (scRNA-seq) measure thousands quantitative, allows unbiased classification cell types. Nevertheless, accuracy cell-type assignment affected data (library complexity, depth, technical errors, noise) proportion messenger (mRNA) molecules successfully converted sequencing. addition, contain quantities mRNAs resulting differences quality, affecting assignment. particularly relevant which, unlike most central system, highly variable size. Cell-type resolution used clustering. aim clustering scRNA-seq identify diverse represent all taxonomies hampered questions "what relation between features function?" type?"152 intimately associated surrounding sheath satellite glial often insufficiently removed sample preparation. Single-nucleus (snRNA-seq) mitigate this. Although cell's genomic accessed nucleus alone, there less starting material cytosol included leading lower median number genes detected per presence ambient confounding classification. Gene capture vital metric, although ease improved snRNA-seq increasing analyzed cells, biological function lost due detection smaller expressed cell. Because this, always favored generated will review focus results obtained method. published heterogeneity mouse dorsal root ganglion (DRG),14,60-62,114,137,151 trigeminal,65,91,145 jugular60 neurons, lack efforts integrate find recurrent populations across using computational strategies. purpose, intersample mapping propagate machine deep-learning neural correlates studies60,61,131,151 well study DRG Sharma et al.114 know sequenced studies, taxonomy heavily influenced revealed studies. 3. Strategy along axis General present trigeminal ganglia, superior inferior (jugular) ganglia glossopharyngeal vagal nerves, DRG, very small geniculate ganglion.19,133 some accessory may XIth cranial nerve. located face oral cavity (including dura mater teeth, respectively), lips mouth having greatest representation. Neurons jugular innervate parts head, ear, throat cutaneous deep rest body. detect relay conscious sensations, visceral largely regulating homeostasis related organ transmitting gustatory taste buds.60,79,136,140 These petrosal nodose dedicated ganglia. Comparing trigeminal, jugular, identified suggests neuronal conserved axis, represented completely neurons.60 colonic neurons43 suggesting innervation. yet compared sets strategies, thus, similarities remain explored. 4. Overview their putative Based presented here, 19 predicted. An overview expression transducers, percent contribution ganglion, key markers, outlined Figure figure shows hierarchical adult transcription factors growth factor receptors known drive diversification development. Interestingly, reflects ontogeny.Figure 1.: Molecular relationship data. Usoskin al. (2015), Zeisel (2018), (2020), nomenclature follows Ernfors (2020) indicated at end branch tree. first top box represents conflation hierarchically summarizing type (C, Aδ, Aβ), modalities evidenced experimentation predicted (M, mechanical; H, heat; HTMR, mechanoreceptor; LTMR, low-threshold mechanoreceptor). Boxes bottom: type, major transduction expressed, percentage representation among innervation targets, examples finally neurons. Question mark indicates prediction expression. Note reflect ontogeny tree receptors. neurogenic Neurogenin-2 (Ngn2) drives early neurogenesis generating Aδ nociceptor, Aβ proprioceptor diversify transcriptional activation, repression, signaling Trk Ret Neurogenin-1 responsible later born defined Runx1, Prdm12, TrkA mostly unmyelinated pruriceptive Nppb, natriuretic peptide precursor B; scRNA-seq, sequencing; Sst, somatostatin.Neurons atlas mechanoreceptors 1 Aδ-LTMR, rapidly adapting (RA) slowly (SA) proprioceptor, C-LTMR, showing overall consistency units explored human.2,38,154 focusing LTMRs, interesting note 2 seem separate LTMRs types: rate adaptation velocity. underlying could mutually exclusive entities defining LTMR A-LTMRs does termination morphology. RA-LTMR scRNA-sequencing,114,131,151 terminates longitudinal lanceolate endings follicles Meissner Pacinian corpuscles.38 SA-LTMR terminate either putatively circumferential follicles. Machine learning–based analyses al.,131 al.,151 al., 2021114,131,151 (from now refer "Usoskin," "Zeisel," "Sharma" brevity) independently nociceptor pruriceptor varying resolution. low-resolution view reveals divisions whereas high individual subtypes identified. At resolution, 14 nociceptors pruriceptors C-fiber Aδ-fiber properties. conflated 7 relationships. We believe functionally similar many transducers Trpm8, Trpv1, Trpm2, Trpm3, Piezo2, multitude consistent both high-resolution taxonomy. following nomenclature: TrpM8high, PEP1-3, NP1-3. full includes 3 "TrpM8" 4 mechano-heat (peptidergic "PEP1" neurons), Aδ-nociceptor (putative heat peptidergic "PEP2" (A-HTMR) "PEP3" Mrgprd+ withdrawal β-alanine (nociceptor "NP1" Mrgpra3 "NP2" somatostatin (Sst) B (Nppb) expressing allergic possibly "NP3" neurons) (Fig. 1). units, shown. PEP1 subtypes, demonstrated one Conversely, proprioceptive neurons,114,131,151 heterogeneity, corresponding Ia, Ib, II endings.95,144 Mrgprb4 described135 It embedded NP2 neurons72 fails scarcity. Better additional expected cells. 5. Cross-species nonhuman primate (NHP, rhesus macaque) scRNA-seq.61 Integration co-clustering learning comparisons high-quality NHP species, basal layout species.61 looking level observed, directly relate stimuli. Transcriptomic analysis human performed spatial transcriptomics128 snRNA-seq.90 There validated transcriptomics. Therefore, transcriptomics extensively analyzed.128 Nguyen al.90 15 clusters (predicted H1-H15) mouse–human counterparts variably co-clustering. mapped back any counterpart (H4 H12 clusters), others showed resemblance (H1, H2, H5 corresponded C-polymodal subtypes; H8 TrpM8high neurons; H9 PEP3; H10 NP1; H11 NP3; H13 Aδ-LTMRs; H14 Aβ-LTMRs; H15 proprioceptors; C-LTMRs found), markers inconsistencies observed comparison. give indication somatosensation; however, further needed understand exact makeup. NHP, current open shaping physiology. Below describe where laboratories strategies120,138,156 summarize those interested interactive reading, single web site option select nomenclatures ("Usoskin," "Sharma") querying gene (https://ernforsgroup.shinyapps.io/MouseDRGNeurons/) containing STRT2 SmartSeq2 macaque (https://ernforsgroup.shinyapps.io/macaquedrg/). Expression makes sense placed Thus, understanding goes wrong chronic pain. centered rather than disproportionate impact examining genetic ablation synthetic inactivation optogenetics chemogenetics mice. reviews topic.2,3,45,70,87,94,112Figure 2.: Schematic "Sharma," "Kupari Usoskin" nomenclatures. mechanoreceptor. NA, available.6. C-cold-sensing Mouse named "high" (PEP3, see below) another expresses level. small-sized critical importantly sensing They esophagus,56,150 representing 6% 8% neurons.21 Trpm8 Foxp2 lacks mechanosensitive channel Piezo2 heat-sensitive TRP channels (ie, Trpa1, Trpm3). neuron, subtypes. difference strategy types.61 myelination, C fiber.151 Whether distinguished remains Intriguingly, Trpm8+ Ca2+ imaging: temperatures (28-20°C), (<18°C), third hybrid response.148 Consistent unimodality knockout TRPM8 transducer mouse.4,17,22 Mice lacking display clearly reduced aversive toward indicating ion contributes to, for, ablating entire population leads complete loss sensitivity mice knocked out.57,87,101 highlight significant role sensing, simultaneously participate independent conclusion supported set experiments. Low-threshold cold-sensitive unimodal stimuli.76 Among Scn10a (Nav1.8). Consistently, deleting Nav1.8 no effect down 5°C extreme (below freezing) absent.73 Moreover, (CGRP) Scn10a+ unknown TRPM8-independent "silent" sensitized neuropathic allodynia.75 proposed alternative transducers11,76 helped identifying remaining Trpm8-null mice, furthermore, below freezing seems regardless tissue damage.118 Finally, take part cold-induced analgesia, suppress pain.103 7. C-mechano-pruriceptors NP1, NP2, NP3 classes mechanosensory reflexes, potentially nociception. express thermosensitive and, according recordings least sensitive, vivo humans negligible.13,37,45,55,66,101 NP1 closer other.61,151 chemosensitive Trpv1 Trpa1 NP-class signal histamine nonhistamine itch-inducing compounds sensors.53,143 Forced MrgprdCre lineage NP3) generate place naive animals.139 none NP bona fide nociceptors, ie, encode stimuli.139 Chemical mediated whose patterns NHP. Exogenous endogenous mediators released damaged infected tissues increase extravasation vessels attracting immune injured response.77 "inflammatory soup" rich purines, amines, cytokines, chemokines, lipid mediators, factors. histamine, serotonin, leukotrienes, prostaglandins, bradykinin, sensitize thereby mediate As below, differentially threshold itch. taxonomy, conducted nociceptors.52,110 8. C-mechanopruriceptor nonpeptidergic NP1-type diameter, Mrgprd superficial layer epidermis glabrous hairy mouse.156 25% 32% pruriception (von Frey). eg, Mrgprd, Mrgprx receptors, Lpar3, Mdfic2. defines define clusters.61 determined. recordings, activated mechanical, chemical, rodents26,66,71,105; evoked von Frey filaments, affect sensation.13,45 they dispensable pinching.44 activating (NP1-3),139 animal,6,139 do after spared injury inflammation (using Freund adjuvant).1,139 state, Still, integrated allodynia especially needs systematically evaluated. mouse, histamine,66 β-alanine, natural pruritogenic compound, binds activates MRGPRD receptor,117 then engages TRPA1 induces itch.141 lysophosphatidic acid receptor Lpar3 mouse. situation, primarily mechanopruriceptive sensors selected pruritogens. NHPs, expression, broader compounds, share described below. 9. C-pruriceptor (chemo) NP2-type occasionally wrapping follicles.25,37,156 cold,37 4% 7% neurons.25,155 itch,37 suggest (see below). show one.114,131,151 dete

Language: Английский

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Scalable generation of sensory neurons from human pluripotent stem cells

Stem Cell Reports, Journal Year: 2023, Volume and Issue: 18(4), P. 1030 - 1047

Published: April 1, 2023

Development of new non-addictive analgesics requires advanced strategies to differentiate human pluripotent stem cells (hPSCs) into relevant cell types. Following principles developmental biology and translational applicability, here we developed an efficient stepwise differentiation method for peptidergic non-peptidergic nociceptors. By modulating specific signaling pathways, hPSCs were first converted SOX10

Language: Английский

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Personalized treatment of neuropathic pain: Where are we now?

European Journal of Pain, Journal Year: 2023, Volume and Issue: 27(9), P. 1084 - 1098

Published: April 28, 2023

Abstract Background The treatment of neuropathic pain remains a major unmet need that the development personalized and refined strategies may contribute to address. Database In this narrative review, we summarize various approaches based on objective biomarkers or clinical markers could be used. Results principle, validation would most robust approach. However, although promising results have been reported demonstrating potential value genomics, anatomical functional markers, these has only just begun. Thus, documented date markers. particular, many studies suggested identification specific subgroups patients presenting with combinations symptoms signs relevant Two main used identify sensory profiles: quantitative testing outcomes description qualities. Conclusion We discuss here advantages limitations approaches, which are not mutually exclusive. Significance Recent data indicate new predictive biological and/or helpful better therefore improve management pain.

Language: Английский

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