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1.
Molecules ; 26(4)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546181

RESUMO

Capsaicin is a potent agonist of the TRPV1 channel, a transduction channel that is highly expressed in nociceptive fibers (pain fibers) throughout the peripheral nervous system. Given the importance of TRPV1 as one of several transduction channels in nociceptive fibers, much research has been focused on the potential therapeutic benefits of using TRPV1 antagonists for the management of pain. However, an antagonist has two limitations. First, an antagonist in principle generally only affects one receptor. Secondly, most antagonists must have an ongoing presence on the receptor to have an effect. Capsaicin overcomes both liabilities by disrupting peripheral terminals of nociceptive fibers that express TRPV1, and thereby affects all of the potential means of activating that pain fiber (not just TRPV1 function). This disruptive effect is dependent on the dose and can occur within minutes. Thus, unlike a typical receptor antagonist, continued bioavailability at the level of the receptor is not necessary. By disrupting the entire terminal of the TRPV1-expressing nociceptive fiber, capsaicin blocks all the activation mechanisms within that fiber, and not just TRPV1 function. Topical capsaicin, an FDA approved treatment for neuropathic pain, addresses pain from abnormal nociceptor activity in the superficial layers of the skin. Effects after a single administration are evident over a period of weeks to months, but in time are fully reversible. This review focuses on the rationale for using capsaicin by injection for painful conditions such as osteoarthritis (OA) and provides an update on studies completed to date.


Assuntos
Capsaicina/uso terapêutico , Neuralgia/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Humanos , Neuralgia/metabolismo , Neuralgia/patologia , Nociceptores/metabolismo , Nociceptores/patologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Canais de Cátion TRPV/metabolismo
2.
Methods Mol Biol ; 2201: 195-198, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32975800

RESUMO

von Frey hairs are important tools for the study of mechanisms of cutaneous stimulation-induced sensory input. Mechanical force is exerted via application of a particular hair to the cutaneous receptive field until buckling of the hair occurs. The most commonly used von Frey filaments are productive in evaluating behavioral responses of neuropathic pain in preclinical and clinical research. To reduce the potential experimenter bias, automated instruments are being developed for behavioral assessment.


Assuntos
Nociceptividade/fisiologia , Medição da Dor/instrumentação , Medição da Dor/métodos , Animais , Modelos Animais de Doenças , Camundongos , Neuralgia , Dor Nociceptiva/fisiopatologia , Nociceptores/metabolismo , Limiar da Dor/fisiologia , Estimulação Física/instrumentação , Ratos
3.
Neuron ; 108(1): 128-144.e9, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32810432

RESUMO

Primary somatosensory neurons are specialized to transmit specific types of sensory information through differences in cell size, myelination, and the expression of distinct receptors and ion channels, which together define their transcriptional and functional identity. By profiling sensory ganglia at single-cell resolution, we find that all somatosensory neuronal subtypes undergo a similar transcriptional response to peripheral nerve injury that both promotes axonal regeneration and suppresses cell identity. This transcriptional reprogramming, which is not observed in non-neuronal cells, resolves over a similar time course as target reinnervation and is associated with the restoration of original cell identity. Injury-induced transcriptional reprogramming requires ATF3, a transcription factor that is induced rapidly after injury and necessary for axonal regeneration and functional recovery. Our findings suggest that transcription factors induced early after peripheral nerve injury confer the cellular plasticity required for sensory neurons to transform into a regenerative state.


Assuntos
Fator 3 Ativador da Transcrição/genética , Reprogramação Celular/genética , Gânglios Espinais/citologia , Regulação da Expressão Gênica/genética , Neuralgia/genética , Traumatismos dos Nervos Periféricos/genética , Células Receptoras Sensoriais/metabolismo , Animais , Axônios , Axotomia , Lesões por Esmagamento/genética , Lesões por Esmagamento/metabolismo , Vértebras Lombares , Mecanorreceptores/metabolismo , Camundongos , Regeneração Nervosa , Plasticidade Neuronal/genética , Nociceptores/metabolismo , RNA-Seq , Recuperação de Função Fisiológica , Nervo Isquiático/lesões , Nervo Isquiático/cirurgia , Análise de Célula Única , Nervos Espinhais/lesões , Nervos Espinhais/cirurgia , Transcriptoma
4.
Pain ; 161(11): 2494-2501, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32826754

RESUMO

SARS-CoV-2 has created a global crisis. COVID-19, the disease caused by the virus, is characterized by pneumonia, respiratory distress, and hypercoagulation and can be fatal. An early sign of infection is loss of smell, taste, and chemesthesis-loss of chemical sensation. Other neurological effects of the disease have been described, but not explained. It is now apparent that many of these neurological effects (for instance joint pain and headache) can persist for at least months after infection, suggesting a sensory neuronal involvement in persistent disease. We show that human dorsal root ganglion (DRG) neurons express the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 at the RNA and protein level. We also demonstrate that SARS-CoV-2 and coronavirus-associated factors and receptors are broadly expressed in human DRG at the lumbar and thoracic level as assessed by bulk RNA sequencing. ACE2 mRNA is expressed by a subset of nociceptors that express MRGPRD mRNA, suggesting that SARS-CoV-2 may gain access to the nervous system through entry into neurons that form free nerve endings at the outermost layers of skin and luminal organs. Therefore, DRG sensory neurons are a potential target for SARS-CoV-2 invasion of the peripheral nervous system, and viral infection of human nociceptors may cause some of the persistent neurological effects seen in COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/metabolismo , Gânglios Espinais/metabolismo , Doenças do Sistema Nervoso/metabolismo , Nociceptores/metabolismo , Peptidil Dipeptidase A/biossíntese , Pneumonia Viral/metabolismo , Glicoproteína da Espícula de Coronavírus/biossíntese , Adulto , Idoso , Infecções por Coronavirus/genética , Feminino , Gânglios Espinais/virologia , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/virologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Glicoproteína da Espícula de Coronavírus/genética
5.
Proc Natl Acad Sci U S A ; 117(26): 15281-15292, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32546520

RESUMO

Whether G protein-coupled receptors signal from endosomes to control important pathophysiological processes and are therapeutic targets is uncertain. We report that opioids from the inflamed colon activate δ-opioid receptors (DOPr) in endosomes of nociceptors. Biopsy samples of inflamed colonic mucosa from patients and mice with colitis released opioids that activated DOPr on nociceptors to cause a sustained decrease in excitability. DOPr agonists inhibited mechanically sensitive colonic nociceptors. DOPr endocytosis and endosomal signaling by protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) pathways mediated the sustained inhibitory actions of endogenous opioids and DOPr agonists. DOPr agonists stimulated the recruitment of Gαi/o and ß-arrestin1/2 to endosomes. Analysis of compartmentalized signaling revealed a requirement of DOPr endocytosis for activation of PKC at the plasma membrane and in the cytosol and ERK in the nucleus. We explored a nanoparticle delivery strategy to evaluate whether endosomal DOPr might be a therapeutic target for pain. The DOPr agonist DADLE was coupled to a liposome shell for targeting DOPr-positive nociceptors and incorporated into a mesoporous silica core for release in the acidic and reducing endosomal environment. Nanoparticles activated DOPr at the plasma membrane, were preferentially endocytosed by DOPr-expressing cells, and were delivered to DOPr-positive early endosomes. Nanoparticles caused a long-lasting activation of DOPr in endosomes, which provided sustained inhibition of nociceptor excitability and relief from inflammatory pain. Conversely, nanoparticles containing a DOPr antagonist abolished the sustained inhibitory effects of DADLE. Thus, DOPr in endosomes is an endogenous mechanism and a therapeutic target for relief from chronic inflammatory pain.


Assuntos
Leucina Encefalina-2-Alanina/farmacologia , Inflamação/complicações , Dor/tratamento farmacológico , Dor/metabolismo , Receptores Opioides delta/agonistas , Animais , Colo/inervação , Leucina Encefalina-2-Alanina/administração & dosagem , Células HEK293 , Humanos , Camundongos , Nanopartículas/administração & dosagem , Neurônios , Nociceptores/metabolismo , Receptores Opioides delta/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
6.
Brain Behav Immun ; 89: 559-568, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32497778

RESUMO

The SARS-CoV-2 virus infects cells of the airway and lungs in humans causing the disease COVID-19. This disease is characterized by cough, shortness of breath, and in severe cases causes pneumonia and acute respiratory distress syndrome (ARDS) which can be fatal. Bronchial alveolar lavage fluid (BALF) and plasma from mild and severe cases of COVID-19 have been profiled using protein measurements and bulk and single cell RNA sequencing. Onset of pneumonia and ARDS can be rapid in COVID-19, suggesting a potential neuronal involvement in pathology and mortality. We hypothesized that SARS-CoV-2 infection drives changes in immune cell-derived factors that then interact with receptors expressed by the sensory neuronal innervation of the lung to further promote important aspects of disease severity, including ARDS. We sought to quantify how immune cells might interact with sensory innervation of the lung in COVID-19 using published data from patients, existing RNA sequencing datasets from human dorsal root ganglion neurons and other sources, and a genome-wide ligand-receptor pair database curated for pharmacological interactions relevant for neuro-immune interactions. Our findings reveal a landscape of ligand-receptor interactions in the lung caused by SARS-CoV-2 viral infection and point to potential interventions to reduce the burden of neurogenic inflammation in COVID-19 pulmonary disease. In particular, our work highlights opportunities for clinical trials with existing or under development rheumatoid arthritis and other (e.g. CCL2, CCR5 or EGFR inhibitors) drugs to treat high risk or severe COVID-19 cases.


Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Pulmão/imunologia , Pulmão/inervação , Pneumonia Viral/imunologia , Receptores de Citocinas/imunologia , Células Receptoras Sensoriais/imunologia , Antirreumáticos/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Citocinas/metabolismo , Bases de Dados Factuais , Gânglios Espinais , Humanos , Pulmão/metabolismo , Pulmão/fisiopatologia , Terapia de Alvo Molecular , Nociceptores/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , RNA-Seq , Receptores de Citocinas/metabolismo , /metabolismo , Células Receptoras Sensoriais/metabolismo , Transcriptoma , Regulação para Cima
7.
J Leukoc Biol ; 108(1): 267-281, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32421901

RESUMO

Psoriasis is a common, chronic multifactorial inflammatory skin disease with both genetic and environmental components. A number of studies have suggested that psoriasis episodes are often preceded by stressful life events. Nevertheless, the underline mechanisms of stress in psoriasis remain unexplored. To address this question, we established an emotional stress mouse model induced by empty bottle stimulation, and applied imiquimod (IMQ), a ligand of TLR7/8 and effective potent immune activator, on the dorsal skin to induce psoriasis-like lesions. We found that empty bottles induced emotional stress exaggerated and prolonged psoriasiform dermatitis, which appeared as more prominent epidermal hyperplasia in the emotional stress mice compared with the control mice. Higher mRNA expression of Il-1ß, Il-17a, and Il-22, as well as higher secretion of IL-1ß, IL-12p40, IL-17, and IL-22 were observed in the skin lesion of emotional stress mice. The emotional stress condition and IMQ treatment synergistically led to higher expression levels of neurotransmitters and their receptors in the skin, especially substance P (SP), we also found that SP could stimulate DCs to secrete more IL-23p40 in vitro. In addition, NK-1R antagonist partially abrogated enhanced epidermal thickness and the level of neurotransmitters in emotional stress mice. Taken together, these results indicate that stress exacerbates and prolongs psoriasiform dermatitis in mice by up-regulating IL-1ß and IL-23p40, which were related to local DCs stimulated by abnormal SP.


Assuntos
Epiderme/patologia , Imiquimode/efeitos adversos , Subunidade p40 da Interleucina-12/biossíntese , Interleucina-1beta/biossíntese , Psoríase/induzido quimicamente , Estresse Psicológico/complicações , Animais , Ansiedade/etiologia , Ansiedade/patologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/patologia , Dermatite/etiologia , Dermatite/patologia , Emoções , Epiderme/efeitos dos fármacos , Hiperplasia , Inflamação/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Neurotransmissores/metabolismo , Nociceptores/metabolismo , Psoríase/complicações , Psoríase/patologia , Receptores da Neurocinina-1/metabolismo , Substância P/metabolismo , Regulação para Cima/efeitos dos fármacos
8.
J Neurosci ; 40(18): 3517-3532, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32245829

RESUMO

One of the first signs of viral infection is body-wide aches and pain. Although this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization is well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-ß) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double-stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENT It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type I interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity.


Assuntos
Viroses do Sistema Nervoso Central/metabolismo , Interferon Tipo I/toxicidade , Nociceptores/metabolismo , Limiar da Dor/fisiologia , Dor/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Animais , Células Cultivadas , Viroses do Sistema Nervoso Central/induzido quimicamente , Viroses do Sistema Nervoso Central/patologia , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Nociceptores/efeitos dos fármacos , Nociceptores/patologia , Dor/induzido quimicamente , Dor/patologia , Limiar da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia
9.
Am J Pathol ; 190(7): 1530-1544, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32246920

RESUMO

HIV-associated sensory neuropathy is a common neurologic comorbidity of HIV infection and prevails in the post-antiretroviral therapy (ART) era. HIV infection drives pathologic changes in the dorsal root ganglia (DRG) through inflammation, altered metabolism, and neuronal dysfunction. Herein, we characterized specific neuronal populations in an SIV-infected macaque model with or without ART. DRG neuronal populations were identified by neurofilament H-chain 200, I-B4 isolectin (IB4), or tropomyosin receptor kinase A expression and assessed for cell body diameter, population size, apoptotic markers, and regeneration signaling. IB4+ and tropomyosin receptor kinase A-positive neurons showed a reduced cell body size (atrophy) and decreased population size (cell death) in the DRG of SIV-infected animals compared with uninfected animals. IB4+ nonpeptidergic neurons were less affected in the presence of ART. DRG neurons showed accumulation of cleaved caspase 3 (apoptosis) and nuclear-localized activating transcription factor 3 (regeneration) in SIV infection, which was significantly lower in uninfected animals and SIV-infected animals receiving ART. Nonpeptidergic neurons predominantly colocalized with cleaved caspase 3 staining. Nonpeptidergic and peptidergic neurons colocalized with nuclear-accumulated activating transcription factor 3, showing active regeneration in sensory neurons. These data suggest that nonpeptidergic and peptidergic neurons are susceptible to pathologic changes from SIV infection, and intervention with ART did not fully ameliorate damage to the DRG, specifically to peptidergic neurons.


Assuntos
Atrofia/patologia , Nociceptores/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Animais , Antirretrovirais/farmacologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Lectinas/metabolismo , Macaca mulatta , Masculino , Nociceptores/efeitos dos fármacos , Nociceptores/metabolismo , Polineuropatias/patologia , Polineuropatias/virologia , Receptor trkA/metabolismo , Vírus da Imunodeficiência Símia
10.
Cell ; 180(5): 956-967.e17, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32084332

RESUMO

Mechanotransduction, the conversion of mechanical stimuli into electrical signals, is a fundamental process underlying essential physiological functions such as touch and pain sensing, hearing, and proprioception. Although the mechanisms for some of these functions have been identified, the molecules essential to the sense of pain have remained elusive. Here we report identification of TACAN (Tmem120A), an ion channel involved in sensing mechanical pain. TACAN is expressed in a subset of nociceptors, and its heterologous expression increases mechanically evoked currents in cell lines. Purification and reconstitution of TACAN in synthetic lipids generates a functional ion channel. Finally, a nociceptor-specific inducible knockout of TACAN decreases the mechanosensitivity of nociceptors and reduces behavioral responses to painful mechanical stimuli but not to thermal or touch stimuli. We propose that TACAN is an ion channel that contributes to sensing mechanical pain.


Assuntos
Canais Iônicos/fisiologia , Mecanotransdução Celular/genética , Nociceptores/metabolismo , Dor/genética , Tato/genética , Animais , Regulação da Expressão Gênica/genética , Humanos , Canais Iônicos/genética , Lipídeos/genética , Camundongos , Camundongos Knockout , Dor/fisiopatologia , Técnicas de Patch-Clamp , Estresse Mecânico , Tato/fisiologia
11.
Int J Mol Sci ; 21(1)2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31948011

RESUMO

Pain in trigeminal areas is driven by nociceptive trigeminal afferents. Transduction molecules, among them the nonspecific cation channels transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1), which are activated by endogenous and exogenous ligands, are expressed by a significant population of trigeminal nociceptors innervating meningeal tissues. Many of these nociceptors also contain vasoactive neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P. Release of neuropeptides and other functional properties are frequently examined using the cell bodies of trigeminal neurons as models of their sensory endings. Pathophysiological conditions cause phosphorylation, increased expression and trafficking of transient receptor potential (TRP) channels, neuropeptides and other mediators, which accelerate activation of nociceptive pathways. Since nociceptor activation may be a significant pathophysiological mechanism involved in both peripheral and central sensitization of the trigeminal nociceptive pathway, its contribution to the pathophysiology of primary headaches is more than likely. Metabolic disorders and medication-induced painful states are frequently associated with TRP receptor activation and may increase the risk for primary headaches.


Assuntos
Cefaleia/patologia , Nociceptores/metabolismo , Canais de Receptores Transientes de Potencial/metabolismo , Cálcio/metabolismo , Depressão Alastrante da Atividade Elétrica Cortical , Cefaleia/metabolismo , Humanos , Meninges/metabolismo , Meninges/ultraestrutura , Doenças Metabólicas/complicações , Doenças Metabólicas/patologia , Neurônios/metabolismo , Neuropeptídeos/metabolismo
12.
Hum Mol Genet ; 29(2): 228-237, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31814000

RESUMO

The transient receptor potential vanilloid 1 (TRPV1) protein is a pain receptor that elicits a hot sensation when an organism eats the capsaicin of red chili peppers. This calcium (Ca2+)-permeable cation channel is mostly expressed in the peripheral nervous system sensory neurons but also in the central nervous system (e.g. hippocampus and cortex). Preclinical studies found that TRPV1 mediates behaviors associated with anxiety and depression. Loss of TRPV1 functionality increases expression of genes related to synaptic plasticity and neurogenesis. Thus, we hypothesized that TRPV1 deficiency may modulate Alzheimer's disease (AD). We generated a triple-transgenic AD mouse model (3xTg-AD+/+) with wild-type (TRPV1+/+), hetero (TRPV1+/-) and knockout (TRPV1-/-) TRPV1 to investigate the role of TRPV1 in AD pathogenesis. We analyzed the animals' memory function, hippocampal Ca2+ levels and amyloid-ß (Aß) and tau pathologies when they were 12 months old. We found that compared with 3xTg-AD-/-/TRPV1+/+ mice, 3xTg-AD+/+/TRPV1+/+ mice had memory impairment and increased levels of hippocampal Ca2+, Aß and total and phosphorylated tau. However, 3xTg-AD+/+/TRPV1-/- mice had better memory function and lower levels of hippocampal Ca2+, Aß, tau and p-tau, compared with 3xTg-AD+/+/TRPV1+/+ mice. Examination of 3xTg-AD-derived primary neuronal cultures revealed that the intracellular Ca2+ chelator BAPTA/AM and the TRPV1 antagonist capsazepine decreased the production of Aß, tau and p-tau. Taken together, these results suggested that TRPV1 deficiency had anti-AD effects and promoted resilience to memory loss. These findings suggest that drugs or food components that modulate TRPV1 could be exploited as therapeutics to prevent or treat AD.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Cálcio/metabolismo , Transtornos da Memória/metabolismo , Canais de Cátion TRPV/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Canais de Cálcio/metabolismo , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Quelantes/farmacologia , Modelos Animais de Doenças , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Hipocampo/metabolismo , Aprendizagem/efeitos dos fármacos , Transtornos da Memória/genética , Camundongos , Camundongos Knockout , Nociceptores/metabolismo , Nociceptores/patologia , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/genética , Proteínas tau/genética
13.
Physiol Rev ; 100(2): 725-803, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31670612

RESUMO

The transient receptor potential ankyrin (TRPA) channels are Ca2+-permeable nonselective cation channels remarkably conserved through the animal kingdom. Mammals have only one member, TRPA1, which is widely expressed in sensory neurons and in non-neuronal cells (such as epithelial cells and hair cells). TRPA1 owes its name to the presence of 14 ankyrin repeats located in the NH2 terminus of the channel, an unusual structural feature that may be relevant to its interactions with intracellular components. TRPA1 is primarily involved in the detection of an extremely wide variety of exogenous stimuli that may produce cellular damage. This includes a plethora of electrophilic compounds that interact with nucleophilic amino acid residues in the channel and many other chemically unrelated compounds whose only common feature seems to be their ability to partition in the plasma membrane. TRPA1 has been reported to be activated by cold, heat, and mechanical stimuli, and its function is modulated by multiple factors, including Ca2+, trace metals, pH, and reactive oxygen, nitrogen, and carbonyl species. TRPA1 is involved in acute and chronic pain as well as inflammation, plays key roles in the pathophysiology of nearly all organ systems, and is an attractive target for the treatment of related diseases. Here we review the current knowledge about the mammalian TRPA1 channel, linking its unique structure, widely tuned sensory properties, and complex regulation to its roles in multiple pathophysiological conditions.


Assuntos
Sinalização do Cálcio , Mecanotransdução Celular , Nociceptividade , Células Receptoras Sensoriais/metabolismo , Canal de Cátion TRPA1/metabolismo , Sensação Térmica , Animais , Canalopatias/metabolismo , Canalopatias/fisiopatologia , Células Quimiorreceptoras/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Mecanorreceptores/metabolismo , Nociceptores/metabolismo , Dor/metabolismo , Dor/fisiopatologia , Termorreceptores/metabolismo
14.
Proc Natl Acad Sci U S A ; 117(38): 23286-23291, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-31213548

RESUMO

Painful or threatening experiences trigger escape responses that are guided by nociceptive neuronal circuitry. Although some components of this circuitry are known and conserved across animals, how this circuitry is regulated at the genetic and developmental levels is mostly unknown. To escape noxious stimuli, such as parasitoid wasp attacks, Drosophila melanogaster larvae generate a curling and rolling response. Rover and sitter allelic variants of the Drosophila foraging (for) gene differ in parasitoid wasp susceptibility, suggesting a link between for and nociception. By optogenetically activating cells associated with each of for's promoters (pr1-pr4), we show that pr1 cells regulate larval escape behavior. In accordance with rover and sitter differences in parasitoid wasp susceptibility, we found that rovers have higher pr1 expression and increased sensitivity to nociception relative to sitters. The for null mutants display impaired responses to thermal nociception, which are rescued by restoring for expression in pr1 cells. Conversely, knockdown of for in pr1 cells phenocopies the for null mutant. To gain insight into the circuitry underlying this response, we used an intersectional approach and activity-dependent GFP reconstitution across synaptic partners (GRASP) to show that pr1 cells in the ventral nerve cord (VNC) are required for the nociceptive response, and that multidendritic sensory nociceptive neurons synapse onto pr1 neurons in the VNC. Finally, we show that activation of the pr1 circuit during development suppresses the escape response. Our data demonstrate a role of for in larval nociceptive behavior. This function is specific to for pr1 neurons in the VNC, guiding a developmentally plastic escape response circuit.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Reação de Fuga , Larva/crescimento & desenvolvimento , Nociceptores/metabolismo , Animais , Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Temperatura Alta , Larva/genética , Larva/fisiologia , Plasticidade Neuronal , Nociceptividade , Regiões Promotoras Genéticas , Vespas/fisiologia
15.
Cell ; 180(1): 33-49.e22, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31813624

RESUMO

Gut-innervating nociceptor sensory neurons respond to noxious stimuli by initiating protective responses including pain and inflammation; however, their role in enteric infections is unclear. Here, we find that nociceptor neurons critically mediate host defense against the bacterial pathogen Salmonella enterica serovar Typhimurium (STm). Dorsal root ganglia nociceptors protect against STm colonization, invasion, and dissemination from the gut. Nociceptors regulate the density of microfold (M) cells in ileum Peyer's patch (PP) follicle-associated epithelia (FAE) to limit entry points for STm invasion. Downstream of M cells, nociceptors maintain levels of segmentous filamentous bacteria (SFB), a gut microbe residing on ileum villi and PP FAE that mediates resistance to STm infection. TRPV1+ nociceptors directly respond to STm by releasing calcitonin gene-related peptide (CGRP), a neuropeptide that modulates M cells and SFB levels to protect against Salmonella infection. These findings reveal a major role for nociceptor neurons in sensing and defending against enteric pathogens.


Assuntos
Microbioma Gastrointestinal/fisiologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Nociceptores/fisiologia , Animais , Epitélio/metabolismo , Feminino , Gânglios Espinais/metabolismo , Gânglios Espinais/microbiologia , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nociceptores/metabolismo , Nódulos Linfáticos Agregados/inervação , Nódulos Linfáticos Agregados/metabolismo , Infecções por Salmonella/metabolismo , Salmonella typhimurium/metabolismo , Salmonella typhimurium/patogenicidade , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia
16.
Adv Mater ; 32(6): e1906171, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31833134

RESUMO

Pain-perceptual nociceptors (PPN) are essential sensory neurons that recognize harmful stimuli and can empower the human body to react appropriately and perceive precisely unusual or dangerous conditions in the real world. Furthermore, the sensitization-regulated nociceptors (SRN) can greatly assist pain-sensitive human to reduce pain sensation by normalizing hyperexcitable central neural activity. Therefore, the implementation of PPNs and SRNs in hardware using emerging nanoscale devices can greatly improve the efficiency of bionic medical machines by giving them different sensitivities to external stimuli according to different purposes. However, current most-normal organic/oxide transistors face a great challenge due to channel scaling, especially in the sub-10 nm channel technology. Here, a sub-10 nm indium-tin-oxide transistor with an ultrashort vertical channel as low as ≈3 nm, using sodium alginate bio-polymer electrolyte as gate dielectric, is demonstrated. This device can emulate important characteristics of PPN such as pain threshold, memory of prior injury, and pain sensitization/desensitization. Furthermore, the most intriguing character of SRN can be achieved by tuning the channel thickness. The proposed device can open new avenues for the fascinating applications of next-generation neuromorphic brain-like systems, such as bio-inspired electronic skins and humanoid robots.


Assuntos
Alginatos/química , Nociceptores/metabolismo , Compostos de Estanho/química , Transistores Eletrônicos , Eletrólitos/química , Desenho de Equipamento , Humanos
17.
Brain ; 142(12): 3852-3867, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31742594

RESUMO

The two-pore potassium channel, TRESK has been implicated in nociception and pain disorders. We have for the first time investigated TRESK function in human nociceptive neurons using induced pluripotent stem cell-based models. Nociceptors from migraine patients with the F139WfsX2 mutation show loss of functional TRESK at the membrane, with a corresponding significant increase in neuronal excitability. Furthermore, using CRISPR-Cas9 engineering to correct the F139WfsX2 mutation, we show a reversal of the heightened neuronal excitability, linking the phenotype to the mutation. In contrast we find no change in excitability in induced pluripotent stem cell derived nociceptors with the C110R mutation and preserved TRESK current; thereby confirming that only the frameshift mutation is associated with loss of function and a migraine relevant cellular phenotype. We then demonstrate the importance of TRESK to pain states by showing that the TRESK activator, cloxyquin, can reduce the spontaneous firing of nociceptors in an in vitro human pain model. Using the chronic nitroglycerine rodent migraine model, we demonstrate that mice lacking TRESK develop exaggerated nitroglycerine-induced mechanical and thermal hyperalgesia, and furthermore, show that cloxyquin conversely is able to prevent sensitization. Collectively, our findings provide evidence for a role of TRESK in migraine pathogenesis and its suitability as a therapeutic target.


Assuntos
Mutação com Perda de Função , Transtornos de Enxaqueca/genética , Nociceptividade/fisiologia , Nociceptores/metabolismo , Canais de Potássio/genética , Animais , Sistemas CRISPR-Cas , Modelos Animais de Doenças , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/metabolismo , Nitroglicerina , Medição da Dor , Técnicas de Patch-Clamp , Canais de Potássio/metabolismo
18.
Nat Immunol ; 20(11): 1435-1443, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31591569

RESUMO

Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ nociceptor-MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.


Assuntos
Alérgenos/imunologia , Dermatite Atópica/imunologia , Mastócitos/imunologia , Nociceptores/imunologia , Pyroglyphidae/imunologia , Animais , Comunicação Celular/imunologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Mastócitos/metabolismo , Camundongos Knockout , Nociceptores/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Pele/citologia , Pele/imunologia , Canais de Cátion TRPV/metabolismo , Taquicininas/genética , Taquicininas/metabolismo
19.
PLoS Genet ; 15(10): e1008341, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658255

RESUMO

In order to respond to changing environments and fluctuations in internal states, animals adjust their behavior through diverse neuromodulatory mechanisms. In this study we show that electrical synapses between the ASH primary quinine-detecting sensory neurons and the neighboring ASK neurons are required for modulating the aversive response to the bitter tastant quinine in C. elegans. Mutant worms that lack the electrical synapse proteins INX-18 and INX-19 become hypersensitive to dilute quinine. Cell-specific rescue experiments indicate that inx-18 operates in ASK while inx-19 is required in both ASK and ASH for proper quinine sensitivity. Imaging analyses find that INX-19 in ASK and ASH localizes to the same regions in the nerve ring, suggesting that both sides of ASK-ASH electrical synapses contain INX-19. While inx-18 and inx-19 mutant animals have a similar behavioral phenotype, several lines of evidence suggest the proteins encoded by these genes play different roles in modulating the aversive quinine response. First, INX-18 and INX-19 localize to different regions of the nerve ring, indicating that they are not present in the same synapses. Second, removing inx-18 disrupts the distribution of INX-19, while removing inx-19 does not alter INX-18 localization. Finally, by using a fluorescent cGMP reporter, we find that INX-18 and INX-19 have distinct roles in establishing cGMP levels in ASK and ASH. Together, these results demonstrate that electrical synapses containing INX-18 and INX-19 facilitate modulation of ASH nociceptive signaling. Our findings support the idea that a network of electrical synapses mediates cGMP exchange between neurons, enabling modulation of sensory responses and behavior.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Conexinas/genética , Sinapses Elétricas/genética , Nociceptores/metabolismo , Quinina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , GMP Cíclico/genética , Sinapses Elétricas/efeitos dos fármacos , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/genética , Nociceptores/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
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