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1.
Cell Rep ; 38(10): 110462, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35263589

RESUMO

Nociceptors can fine-tune local or systemic immunity, but the mechanisms of nociceptive modulation in endotoxic death remain largely unknown. Here, we identified C-type lectin Reg3γ as a nociceptor-enriched hormone that protects the host from endotoxic death. During endotoxemia, nociceptor-derived Reg3γ penetrates the brain and suppresses the expression of microglial indoleamine dioxygenase 1, a critical enzyme of the kynurenine pathway, via the Extl3-Bcl10 axis. Endotoxin-administered nociceptor-null mice and nociceptor-specific Reg3γ-deficient mice exhibit a high mortality rate accompanied by decreased brain HK1 phosphorylation and ATP production despite normal peripheral inflammation. Such metabolic arrest is only observed in the brain, and aberrant production of brain quinolinic acid, a neurotoxic metabolite of the kynurenine pathway, causes HK1 suppression. Strikingly, the central administration of Reg3γ protects mice from endotoxic death by enhancing brain ATP production. By identifying nociceptor-derived Reg3γ as a microglia-targeted hormone, this study provides insights into the understanding of tolerance to endotoxic death.


Assuntos
Cinurenina , Microglia , Proteínas Associadas a Pancreatite/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Endotoxinas/metabolismo , Hormônios/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Camundongos , Microglia/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , Nociceptores/metabolismo
2.
Front Immunol ; 13: 812962, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35355986

RESUMO

Chronic pain associated with joint disorders, such as rheumatoid arthritis (RA), osteoarthritis (OA) and implant aseptic loosening (AL), is a highly debilitating symptom that impacts mobility and quality of life in affected patients. The neuroimmune crosstalk has been demonstrated to play a critical role in the onset and establishment of chronic pain conditions. Immune cells release cytokines and immune mediators that can activate and sensitize nociceptors evoking pain, through interaction with receptors in the sensory nerve terminals. On the other hand, sensory and sympathetic nerve fibers release neurotransmitters that bind to their specific receptor expressed on surface of immune cells, initiating an immunomodulatory role. Macrophages have been shown to be key players in the neuroimmune crosstalk. Moreover, macrophages constitute the dominant immune cell population in RA, OA and AL. Importantly, the targeting of macrophages can result in anti-nociceptive effects in chronic pain conditions. Therefore, the aim of this review is to discuss the nature and impact of the interaction between the inflammatory response and nerve fibers in these joint disorders regarding the genesis and maintenance of pain. The role of macrophages is highlighted. The alteration in the joint innervation pattern and the inflammatory response are also described. Additionally, the immunomodulatory role of sensory and sympathetic neurotransmitters is revised.


Assuntos
Artrite Reumatoide , Dor Crônica , Osteoartrite , Artralgia/metabolismo , Artrite Reumatoide/metabolismo , Dor Crônica/metabolismo , Humanos , Macrófagos , Nociceptores/metabolismo , Osteoartrite/metabolismo , Qualidade de Vida
3.
Int Immunopharmacol ; 107: 108700, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35313271

RESUMO

Pain is an unpleasant sensation associated with injury, inflammation, and infection. It has been demonstrated that communication between immune cells and neurons plays a vital role in pain and pain-related diseases (e.g. multiple sclerosis, osteoarthritis, irritable bowel syndrome). Growing data from preclinical and clinical studies have established that the bilateral regulations between peripheral immune cells and nociceptive neurons could be beneficial or detrimental for the development of pain and immune defense. We here review the mechanisms underlying neuroimmune crosstalk between circulating immune cells (e.g. macrophages, T cells, mast cells, neutrophils, monocytes) and nociceptors in the peripheral nervous system and the spinal cord. Deciphering the mechanisms by which neuroimmune interaction integrates neuronal inputs and immune responses helps to understand the pathogenesis of pain-related diseases and develop effective medications.


Assuntos
Nociceptores , Dor , Humanos , Neuroimunomodulação , Nociceptores/fisiologia , Sistema Nervoso Periférico , Medula Espinal
4.
J Mater Chem B ; 10(12): 1991-2000, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35233588

RESUMO

The sensations of touch and pain are fundamental components of our daily life, which can transport vital information about the surroundings and provide protection to our bodies. In this study, the transmission process of sensing pressure stimuli to dorsal root neurons (nociceptors) was simulated using electronic devices. In this regard, we proposed and experimentally demonstrated a biomimetic nociceptor system with tactile perception. In this system, the sensing paper as E-skin simulates the biological skin to sense external pressure stimulation and generate electrical signals, while the threshold switching memristor simulates the biological nociceptor to receive and process the receptor signals. The W/VO2/Pt memristor exhibits all key features of nociceptors including threshold, relaxation, "no adaptation" and sensitization phenomena of allodynia and hyperalgesia. The E-skin shows high sensitivity and a broad sensing range and is capable of monitoring different human movements and physiological signals. With the bio-inspired artificial tactile nociceptive system, the threshold and sensitization properties under pressure stimuli are obtained successfully. Notably, this system could be used as an artificial tactile alarm system to demonstrate the potential applicability of humanoid robots. Thus, the present work is of great significance to the development of hardware architecture in artificial intelligence systems and replacement neuroprosthetics.


Assuntos
Nociceptores , Dispositivos Eletrônicos Vestíveis , Inteligência Artificial , Eletrônica , Humanos , Tato/fisiologia
5.
Proc Natl Acad Sci U S A ; 119(12): e2113645119, 2022 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-35294287

RESUMO

Acute nociception is essential for survival by warning organisms against potential dangers, whereas tissue injury results in a nociceptive hypersensitivity state that is closely associated with debilitating disease conditions, such as chronic pain. Transient receptor potential (Trp) ion channels expressed in nociceptors detect noxious thermal and chemical stimuli to initiate acute nociception. The existing hypersensitivity model suggests that under tissue injury and inflammation, the same Trp channels in nociceptors are sensitized through transcriptional and posttranslational modulation, leading to nociceptive hypersensitivity. Unexpectedly and different from this model, we find that in Drosophila larvae, acute heat nociception and tissue injury-induced hypersensitivity involve distinct cellular and molecular mechanisms. Specifically, TrpA1-D in peripheral sensory neurons mediates acute heat nociception, whereas TrpA1-C in a cluster of larval brain neurons transduces the heat stimulus under the allodynia state. As a result, interfering with synaptic transmission of these brain neurons or genetic targeting of TrpA1-C blocks heat allodynia but not acute heat nociception. TrpA1-C and TrpA1-D are two splicing variants of TrpA1 channels and are coexpressed in these brain neurons. We further show that Gq-phospholipase C signaling, downstream of the proalgesic neuropeptide Tachykinin, differentially modulates these two TrpA1 isoforms in the brain neurons by selectively sensitizing heat responses of TrpA1-C but not TrpA1-D. Together, our studies provide evidence that nociception and noncaptive sensitization could be mediated by distinct sensory neurons and molecular sensors.


Assuntos
Nociceptividade , Canais de Potencial de Receptor Transitório , Animais , Drosophila/fisiologia , Neurônios , Nociceptividade/fisiologia , Nociceptores/fisiologia , Transdutores , Canais de Potencial de Receptor Transitório/genética
6.
STAR Protoc ; 3(2): 101187, 2022 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-35330962

RESUMO

Human pluripotent stem cells (hPSCs) show promise for studying diseases affecting cell populations that are not easily available, including sensory neurons (SNs). Here, we present a differentiation protocol in chemically defined conditions to generate peripheral SNs from hPSCs. We describe four main steps: expansion of hPSCs, neural crest cell (NCC) differentiation, NCC dissociation and replating, and sensory neuron (SN) differentiation. This protocol enables generation of a mechanoreceptor-enriched culture or a population containing all three SN subtypes (nociceptors, mechanoreceptors, and proprioceptors). For complete details on the use and execution of this protocol, please refer to Saito-Diaz et al. (2021).


Assuntos
Nociceptores , Células-Tronco Pluripotentes , Técnicas de Cultura de Células/métodos , Humanos , Mecanorreceptores , Células Receptoras Sensoriais
7.
Small ; 18(14): e2103364, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35195345

RESUMO

The sensory nervous and immune systems work in concert to preserve homeostasis. While this endogenous interplay protects from danger, it may drive chronic pathologies. Currently, genetic engineering of neurons remains the primary approach to interfere selectively with this potentially deleterious interplay. However, such manipulations are not feasible in a clinical setting. Here, this work reports a nanotechnology-enabled concept to silence subsets of unmodified nociceptor neurons that exploits their ability to respond to heat via the transient receptor potential vanilloid type 1 (TRPV1) channel. This strategy uses laser stimulation of antibody-coated gold nanoparticles to heat-activate TRPV1, turning this channel into a cell-specific drug-entry port. This delivery method allows transport of a charged cationic derivative of an N-type calcium channel blocker (CNCB-2) into targeted sensory fibers. CNCB-2 delivery blocks neuronal calcium currents and neuropeptides release, resulting in targeted silencing of nociceptors. Finally, this work demonstrates the ability of the approach to probe neuro-immune crosstalk by targeting cytokine-responsive nociceptors and by successfully preventing nociceptor-induced CD8+ T-cells polarization. Overall, this work constitutes the first demonstration of targeted silencing of nociceptor neuron subsets without requiring genetic modification, establishing a strategy for interfering with deleterious neuro-immune interplays.


Assuntos
Nanopartículas Metálicas , Nociceptores , Linfócitos T CD8-Positivos , Gânglios Espinais , Ouro , Neurônios , Nociceptores/fisiologia , Canais de Cátion TRPV
8.
Neuron ; 110(4): 559-561, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-35176237

RESUMO

Transfer between cells is an unexpected addition to the mitochondrial life cycle. In this issue of Neuron, Van der Vlist et al. now provide evidence that M2-macrophages infiltrating sensory ganglia resolve pain by transferring particles containing mitochondria to neurons-thus boosting nociceptors back to normal function.


Assuntos
Gânglios Espinais , Nociceptores , Gânglios Espinais/citologia , Humanos , Mitocôndrias , Neurônios , Nociceptores/metabolismo , Dor/fisiopatologia
9.
Mol Pain ; 18: 17448069221080305, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35189759

RESUMO

Nervous system manifestations caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of great concern. Neurological symptoms and the neurological effects induced by SARS-CoV-2, such as the loss of various sensory perceptions, indicate direct viral invasion into sensory neurons. Therefore, it is very important to identify the distribution of angiotensin-converting enzyme 2 (ACE2), the receptor of SARS-CoV-2, in human nervous system. However, autofluorescence from lipofuscin obviously impacted immunofluorescence analysis in previous studies. We demonstrated that Sudan Black B (SBB) remarkably reduced the massive lipofuscin-like autofluorescence and the immunofluorescence signal would be sharpened following the exposure compensation. Additionally, we confirmed that ACE2 was expressed in IB4+, CGRP+, and NF200+ sensory subpopulations. The mapping of ACE2 distribution in hDRG would facilitate the understanding of sensory disorder induced by SARS-CoV-2.


Assuntos
COVID-19 , Peptidil Dipeptidase A , Angiotensinas , Compostos Azo , Humanos , Naftalenos , Nociceptores , Peptidil Dipeptidase A/fisiologia , SARS-CoV-2
10.
Nat Commun ; 13(1): 728, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-35132099

RESUMO

Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. However, how presynaptic NMDARs (PreNMDARs) in spinal nociceptor terminals control presynaptic plasticity and pain hypersensitivity has remained unclear. Here we report that PreNMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner. PreNMDARs depresses presynaptic transmission in basal state, while paradoxically causing presynaptic potentiation upon injury. This state-dependent modulation is dependent on Ca2+ influx via PreNMDARs. Small conductance Ca2+-activated K+ (SK) channels are responsible for PreNMDARs-mediated synaptic depression. Rather, tissue inflammation induces PreNMDARs-PKG-I-dependent BDNF secretion from spinal nociceptor terminals, leading to SK channels downregulation, which in turn converts presynaptic depression to potentiation. Our findings shed light on the state-dependent characteristics of PreNMDARs in spinal nociceptor terminals on modulating nociceptive transmission and revealed a mechanism underlying state-dependent transition. Moreover, we identify PreNMDARs in spinal nociceptor terminals as key constituents of activity-dependent pain sensitization.


Assuntos
Dor Crônica/fisiopatologia , Nociceptores/metabolismo , Terminações Pré-Sinápticas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cálcio/metabolismo , Dor Crônica/genética , Dor Crônica/metabolismo , Proteína Quinase Dependente de GMP Cíclico Tipo I/genética , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Gânglios Espinais/citologia , Gânglios Espinais/fisiologia , Inflamação , Potenciação de Longa Duração , Depressão Sináptica de Longo Prazo , Camundongos , Camundongos Transgênicos , Substância Cinzenta Periaquedutal/citologia , Substância Cinzenta Periaquedutal/fisiologia , Canais de Potássio Cálcio-Ativados/genética , Canais de Potássio Cálcio-Ativados/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Transmissão Sináptica
11.
Small ; 18(16): e2200185, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35218611

RESUMO

The switching variability caused by intrinsic stochasticity of the ionic/atomic motions during the conductive filaments (CFs) formation process largely limits the applications of diffusive memristors (DMs), including artificial neurons, neuromorphic computing and artificial sensory systems. In this study, a DM device with improved device uniformity based on well-crystallized two-dimensional (2D) h-BN, which can restrict the CFs formation from three to two dimensions due to the high migration barrier of Ag+ between h-BN interlayer, is developed. The BN-DM has potential arrayable feature with high device yield of 88%, which can be applied for building a reservoir computing system for digital pattern recognition with high accuracy rate of 96%, and used as an artificial nociceptor to sense the external noxious stimuli and mimic the important biological nociceptor properties. By connecting the BN-DM to a self-made triboelectric nanogenerator (TENG), a self-power mechano-nociceptor system, which can successfully mimic the important nociceptor features of "threshold", "relaxation" and "allodynia" is designed.


Assuntos
Síndrome de Fadiga Crônica , Nociceptores , Citoesqueleto , Condutividade Elétrica , Humanos , Neurônios
12.
J Neurosci ; 42(13): 2690-2700, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35169019

RESUMO

DRG neurons are classified into distinct types to mediate the somatosensation with different modalities. Recently, transcriptional profilings of DRG neurons by single-cell RNA-sequencing have provided new insights into the neuron typing and functional properties. Zinc-finger CCHC domain-containing 12 (Zcchc12) was reported to be the representative marker for a subtype of galanin-positive (Gal +) DRG neurons. However, the characteristics and functions of Zcchc12 + neurons are largely unknown. Here, we genetically labeled Zcchc12 + neurons in Zcchc12-CreERT2::Ai9 mice, and verified that Zcchc12 represented a new subpopulation of DRG neurons in both sexes. Zcchc12 + neurons centrally innervated the superficial laminae in spinal dorsal horn, and peripherally terminated as free nerve endings in the epidermis and cluster-shaped fibers in the dermis of footpads and nearby. In addition, Zcchc12 + neurons also formed circumferential endings surrounding the hair follicles in hairy skin. Functionally, in vivo calcium imaging in DRGs revealed that Zcchc12 + neurons were polymodal nociceptors and could be activated by mechanical and noxious thermal stimuli. Behavioral tests showed that selective ablation of Zcchc12 + DRG neurons reduced the sensitivity to noxious heat in mice. Together, we identified a new subpopulation of Zcchc12 + nociceptors essential for noxious heat sensation.SIGNIFICANCE STATEMENT Zcchc12 represents a new subpopulation of DRG neurons. The characteristics and functions of Zcchc12 + neurons are largely unknown. Here we genetically labeled Zcchc12 + neurons, and showed that the fibers of Zcchc12 + DRG neurons projected to superficial lamina at spinal dorsal horn, and innervated skin as free nerve endings in the epidermis and cluster-shaped fibers in the dermis of footpads and nearby. Functionally, Zcchc12 + DRG neurons responded to noxious mechanical and heat stimuli. Ablation of Zcchc12 + DRG neurons impaired the sensation of noxious heat in mice. Therefore, we identify a new subpopulation of DRG neurons required for noxious heat sensation.


Assuntos
Temperatura Alta , Nociceptores , Animais , Feminino , Gânglios Espinais , Masculino , Camundongos , Nociceptores/fisiologia , Células Receptoras Sensoriais/fisiologia , Corno Dorsal da Medula Espinal , Sensação Térmica
14.
Sci Transl Med ; 14(632): eabj8186, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-35171654

RESUMO

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


Assuntos
Dor Crônica , Nociceptores , Animais , Feminino , Gânglios Espinais/metabolismo , Humanos , Masculino , Camundongos , Nociceptores/metabolismo , Células Receptoras Sensoriais/metabolismo , Transcriptoma/genética
15.
J Neuroinflammation ; 19(1): 7, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34991641

RESUMO

BACKGROUND: Inflammatory visceral pain is endogenously controlled by enkephalins locally released by mucosal CD4+ T lymphocytes in mice. The present study aimed at identifying opioid receptor(s) expressed on nociceptive sensory nerves involved in this peripheral opioid-mediated analgesia. METHODS: The peripheral analgesia associated with the accumulation of CD4+ T lymphocytes within the inflamed colonic mucosa was assessed in conditional knockout mice specifically deleted for either of the two opioid receptors for enkephalins (i.e., µ (MOR) and δ (DOR) receptors) in Nav1.8-expressing sensory neurons in the dextran sulfate sodium (DSS)-induced colitis model. RESULTS: Endogenous analgesia is lost in conditional knockout mice for DOR, but not MOR at the later phase of the DSS-induced colitis. The absence of either of the opioid receptors on sensory nerves had no impact on both the colitis severity and the rate of T lymphocytes infiltrating the inflamed colonic mucosa. CONCLUSION: The key role of DOR on primary afferents in relieving intestinal inflammatory pain opens new therapeutic opportunities for peripherally restricted DOR analgesics to avoid most of the side effects associated with MOR-targeting drugs used in intestinal disorders.


Assuntos
Colite/metabolismo , Mucosa Intestinal/metabolismo , Nociceptores/metabolismo , Receptores Opioides delta/metabolismo , Dor Visceral/metabolismo , Analgesia , Animais , Colite/genética , Modelos Animais de Doenças , Inflamação/genética , Inflamação/metabolismo , Camundongos , Camundongos Knockout , Receptores Opioides delta/genética , Dor Visceral/genética
16.
Proc Natl Acad Sci U S A ; 119(5)2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35074873

RESUMO

The King Baboon spider, Pelinobius muticus, is a burrowing African tarantula. Its impressive size and appealing coloration are tempered by reports describing severe localized pain, swelling, itchiness, and muscle cramping after accidental envenomation. Hyperalgesia is the most prominent symptom after bites from P. muticus, but the molecular basis by which the venom induces pain is unknown. Proteotranscriptomic analysis of P. muticus venom uncovered a cysteine-rich peptide, δ/κ-theraphotoxin-Pm1a (δ/κ-TRTX-Pm1a), that elicited nocifensive behavior when injected into mice. In small dorsal root ganglion neurons, synthetic δ/κ-TRTX-Pm1a (sPm1a) induced hyperexcitability by enhancing tetrodotoxin-resistant sodium currents, impairing repolarization and lowering the threshold of action potential firing, consistent with the severe pain associated with envenomation. The molecular mechanism of nociceptor sensitization by sPm1a involves multimodal actions over several ion channel targets, including NaV1.8, KV2.1, and tetrodotoxin-sensitive NaV channels. The promiscuous targeting of peptides like δ/κ-TRTX-Pm1a may be an evolutionary adaptation in pain-inducing defensive venoms.


Assuntos
Nociceptores/efeitos dos fármacos , Papio/metabolismo , Peptídeos/farmacologia , Venenos de Aranha/farmacologia , Aranhas/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Gânglios Espinais/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Canais Iônicos/metabolismo , Camundongos , Dor/tratamento farmacológico , Tetrodotoxina/farmacologia
17.
J Neural Eng ; 19(1)2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-34996054

RESUMO

Objective.Small area electrodes enable preferential activation of nociceptive fibers. It is debated, however, whether co-activation of large fibers still occurs for the existing electrode designs. Moreover, existing electrodes are limited to low stimulation intensities, for which behavioral and physiological responses may be considered less reliable. A recent optimization study showed that there is a potential for improving electrode performance and increase the range of possible stimulation intensities. Based on those results, the present study introduces and tests a novel planar concentric array electrode design for small fiber activation in healthy volunteers.Approach.Volunteers received electrical stimulation with the planar concentric array electrode and a regular patch electrode. Perception thresholds (PT) were estimated at the beginning and the end of the experiment. Evoked cortical potentials were recorded in blocks of 30 stimuli. For the patch, stimulation current intensity was set to two times PT, while three intensities, two, five, and ten times PT, were applied with the planar concentric array electrode. Sensation quality, numerical-rating scores, and reaction times were obtained for each PT estimation and during each block of evoked potential recordings.Main results.Stimulation with the patch electrode was characterized as dull, while stimulation with the planar concentric array electrode was characterized as sharp, with increased sharpness for increasing stimulus current intensity. Likewise, scores of the numerical rating scale were higher for the planar concentric array electrode compared to the patch and increased with increasing stimulation current intensity. Reaction times and ERP latencies were longer for the planar concentric array electrode compared to the patch.Significance.The presented novel planar concentric array electrode is a small, non-invasive, and single-use electrode that has the potential to investigate small fiber neuropathy and pain mechanisms, as it is small fiber preferential for a wide range of stimulation intensities.


Assuntos
Nociceptores , Pele , Estimulação Elétrica/métodos , Eletrodos , Potenciais Evocados/fisiologia , Humanos , Nociceptores/fisiologia
18.
Nanoscale ; 14(6): 2316-2326, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-35084010

RESUMO

Capable of reflecting the location and intensity of external harmful stimuli, a nociceptor network is of great importance for receiving pain-perception information. However, the hardware-based implementation of a nociceptor network through the use of a transistor array remains a great challenge in the area of brain-inspired neuromorphic applications. Herein, a simple ionotronic junctionless oxide transistor array with pain-perception abilities is successfully realized due to a coplanar-gate proton-coupling effect in sodium alginate biopolymer electrolyte. Several important pain-perception characteristics of nociceptors are emulated, such as a pain threshold, the memory of prior injury, and sensitization behavior due to pathway alterations. In particular, a good graded pain-perception network system has been successfully established through coplanar capacitance and resistance. More importantly, clear polarity reversal of Lorentz-type spatiotemporal pain-perception emulation can be finally realized in our projection-dependent nociceptor network. This work may provide new avenues for bionic medical machines and humanoid robots based on these intriguing pain-perception abilities.


Assuntos
Nociceptores , Óxidos , Biopolímeros , Humanos , Dor , Percepção , Transistores Eletrônicos
19.
J Neurophysiol ; 127(2): 463-473, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35020516

RESUMO

Unmyelinated tactile (C-tactile or CT) afferents are abundant in arm hairy skin and have been suggested to signal features of social affective touch. Here, we recorded from unmyelinated low-threshold mechanosensitive afferents in the peroneal and radial nerves. The most distal receptive fields were located on the proximal phalanx of the third finger for the superficial branch of the radial nerve and near the lateral malleolus for the peroneal nerve. We found that the physiological properties with regard to conduction velocity and mechanical threshold, as well as their tuning to brush velocity, were similar in CT units across the antebrachial (n = 27), radial (n = 8), and peroneal (n = 4) nerves. Moreover, we found that although CT afferents are readily found during microneurography of the arm nerves, they appear to be much more sparse in the lower leg compared with C-nociceptors. We continued to explore CT afferents with regard to their chemical sensitivity and found that they could not be activated by topical application to their receptive field of either the cooling agent menthol or the pruritogen histamine. In light of previous studies showing the combined effects that temperature and mechanical stimuli have on these neurons, these findings add to the growing body of research suggesting that CT afferents constitute a unique class of sensory afferents with highly specialized mechanisms for transducing gentle touch.NEW & NOTEWORHY Unmyelinated tactile (CT) afferents are abundant in arm hairy skin and are thought to signal features of social affective touch. We show that CTs are also present but are relatively sparse in the lower leg compared with C-nociceptors. CTs display similar physiological properties across the arm and leg nerves. Furthermore, CT afferents do not respond to the cooling agent menthol or the pruritogen histamine, and their mechanical response properties are not altered by these chemicals.


Assuntos
Afeto , Antipruriginosos/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Mecanorreceptores/fisiologia , Mentol/farmacologia , Fibras Nervosas Amielínicas/fisiologia , Nervo Fibular/fisiologia , Percepção do Tato/fisiologia , Adulto , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiologia , Antipruriginosos/administração & dosagem , Feminino , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/administração & dosagem , Humanos , Perna (Membro)/inervação , Masculino , Mecanorreceptores/efeitos dos fármacos , Mentol/administração & dosagem , Fibras Nervosas Amielínicas/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Nervo Fibular/efeitos dos fármacos , Nervo Radial/efeitos dos fármacos , Nervo Radial/fisiologia , Percepção do Tato/efeitos dos fármacos , Adulto Jovem
20.
Mol Pain ; 18: 17448069211069255, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35040378

RESUMO

Orofacial pain disorders are predominately experienced by women. Progesterone, a major ovarian hormone, is neuroprotective and antinociceptive. We recently reported that progesterone attenuates estrogen-exacerbated orofacial pain behaviors, yet it remains unclear what anatomical substrate underlies progesterone's activity in the trigeminal system. Progesterone has been reported to exert protective effects through actions at intracellular progesterone receptors (iPR), membrane-progesterone receptors (mPR), or sigma 1 receptors (Sig-1R). Of these, the iPR and Sig-1R have been reported to have a role in pain. Progesterone can also have antinociceptive effects through its metabolite, allopregnanolone. Two enzymes, 5α-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD), are required for the metabolism of progesterone to allopregnanolone. Both progesterone and allopregnanolone rapidly attenuate pain sensitivity, implicating action of either progesterone at Sig-1R and/or conversion to allopregnanolone which targets GABAA receptors. In the present study, we investigated whether Sig-1 Rs are expressed in nociceptors within the trigeminal ganglia of cycling female rats and whether the two enzymes required for progesterone metabolism to allopregnanolone, 5α-reductase and 3α-hydroxysteroid dehydrogenase, are also present. Adult female rats from each stage of the estrous cycle were rapidly decapitated and the trigeminal ganglia collected. Trigeminal ganglia were processed by either fluorescent immunochemistry or western blotting to for visualization and quantification of Sig-1R, 5α-reductase, and 3α-hydroxysteroid dehydrogenase. Here we report that Sig-1Rs and both enzymes involved in progesterone metabolism are highly expressed in a variety of nociceptive sensory neuron populations in the female rat trigeminal ganglia at similar levels across the four stages of the estrous cycle. These data indicate that trigeminal sensory neurons are an anatomical substrate for the reported antinociceptive activity of progesterone via Sig-1R and/or conversion to allopregnanolone.


Assuntos
Nociceptores , Progesterona , Analgésicos , Animais , Feminino , Humanos , Nociceptividade , Nociceptores/metabolismo , Progesterona/metabolismo , Progesterona/farmacologia , Ratos , Receptores sigma , Células Receptoras Sensoriais/metabolismo , Gânglio Trigeminal/metabolismo
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