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1.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540826

RESUMO

Toll-like receptors (TLRs) are key receptors through which infectious and non-infectious challenges act with consequent activation of the inflammatory cascade that plays a critical function in various acute and chronic diseases, behaving as amplification and chronicization factors of the inflammatory response. Previous studies have shown that synthetic analogues of lipid A based on glucosamine with few chains of unsaturated and saturated fatty acids, bind MD-2 and inhibit TLR4 receptors. These synthetic compounds showed antagonistic activity against TLR4 activation in vitro by LPS, but little or no activity in vivo. This study aimed to show the potential use of N-palmitoyl-D-glucosamine (PGA), a bacterial molecule with structural similarity to the lipid A component of LPS, which could be useful for preventing LPS-induced tissue damage or even peripheral neuropathies. Molecular docking and molecular dynamics simulations showed that PGA stably binds MD-2 with a MD-2/(PGA)3 stoichiometry. Treatment with PGA resulted in the following effects: (i) it prevented the NF-kB activation in LPS stimulated RAW264.7 cells; (ii) it decreased LPS-induced keratitis and corneal pro-inflammatory cytokines, whilst increasing anti-inflammatory cytokines; (iii) it normalized LPS-induced miR-20a-5p and miR-106a-5p upregulation and increased miR-27a-3p levels in the inflamed corneas; (iv) it decreased allodynia in peripheral neuropathy induced by oxaliplatin or formalin, but not following spared nerve injury of the sciatic nerve (SNI); (v) it prevented the formalin- or oxaliplatin-induced myelino-axonal degeneration of sciatic nerve. SIGNIFICANCE STATEMENT We report that PGA acts as a TLR4 antagonist and this may be the basis of its potent anti-inflammatory activity. Being unique because of its potency and stability, as compared to other similar congeners, PGA can represent a tool for the optimization of new TLR4 modulating drugs directed against the cytokine storm and the chronization of inflammation.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Glicolipídeos/uso terapêutico , Hiperalgesia/prevenção & controle , Ceratite/tratamento farmacológico , Neuralgia/tratamento farmacológico , Receptor 4 Toll-Like/antagonistas & inibidores , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Glicolipídeos/farmacologia , Células HEK293 , Humanos , Hiperalgesia/etiologia , Ceratite/induzido quimicamente , Ceratite/patologia , Lipopolissacarídeos/toxicidade , Antígeno 96 de Linfócito/metabolismo , Masculino , Camundongos , MicroRNAs/genética , Modelos Moleculares , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Conformação Proteica , Células RAW 264.7 , Distribuição Aleatória , Nervo Isquiático/lesões , Canal de Cátion TRPA1/metabolismo
2.
Nature ; 589(7843): 591-596, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33361809

RESUMO

Haematopoietic stem cells (HSCs) reside in specialized microenvironments in the bone marrow-often referred to as 'niches'-that represent complex regulatory milieux influenced by multiple cellular constituents, including nerves1,2. Although sympathetic nerves are known to regulate the HSC niche3-6, the contribution of nociceptive neurons in the bone marrow remains unclear. Here we show that nociceptive nerves are required for enforced HSC mobilization and that they collaborate with sympathetic nerves to maintain HSCs in the bone marrow. Nociceptor neurons drive granulocyte colony-stimulating factor (G-CSF)-induced HSC mobilization via the secretion of calcitonin gene-related peptide (CGRP). Unlike sympathetic nerves, which regulate HSCs indirectly via the niche3,4,6, CGRP acts directly on HSCs via receptor activity modifying protein 1 (RAMP1) and the calcitonin receptor-like receptor (CALCRL) to promote egress by activating the Gαs/adenylyl cyclase/cAMP pathway. The ingestion of food containing capsaicin-a natural component of chili peppers that can trigger the activation of nociceptive neurons-significantly enhanced HSC mobilization in mice. Targeting the nociceptive nervous system could therefore represent a strategy to improve the yield of HSCs for stem cell-based therapeutic agents.


Assuntos
Vias Autônomas , Movimento Celular , Células-Tronco Hematopoéticas/citologia , Nociceptividade/fisiologia , Nociceptores/fisiologia , Sistema Nervoso Simpático/citologia , Adenilil Ciclases/metabolismo , Animais , Vias Autônomas/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Capsaicina/farmacologia , Movimento Celular/efeitos dos fármacos , AMP Cíclico/metabolismo , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Fator Estimulador de Colônias de Granulócitos/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nociceptividade/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Proteína 1 Modificadora da Atividade de Receptores/metabolismo , Transdução de Sinais/efeitos dos fármacos , Nicho de Células-Tronco , Sistema Nervoso Simpático/efeitos dos fármacos
3.
Sci Rep ; 10(1): 22319, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33339884

RESUMO

Brief thermo-nociceptive stimuli elicit low-frequency phase-locked local field potentials (LFPs) and high-frequency gamma-band oscillations (GBOs) in the human insula. Although neither of these responses constitute a direct correlate of pain perception, previous findings suggest that insular GBOs may be strongly related to the activation of the spinothalamic system and/or to the processing of thermal information. To disentangle these different features of the stimulation, we compared the insular responses to brief painful thermonociceptive stimuli, non-painful cool stimuli, mechano-nociceptive stimuli, and innocuous vibrotactile stimuli, recorded using intracerebral electroencephalograpic activity in 7 epileptic patients (9 depth electrodes, 58 insular contacts). All four types of stimuli elicited consistent low-frequency phase-locked LFPs throughout the insula, possibly reflecting supramodal activity. The latencies of thermo-nociceptive and cool low-frequency phase-locked LFPs were shorter in the posterior insula compared to the anterior insula, suggesting a similar processing of thermal input initiating in the posterior insula, regardless of whether the input produces pain and regardless of thermal modality. In contrast, only thermo-nociceptive stimuli elicited an enhancement of insular GBOs, suggesting that these activities are not simply related to the activation of the spinothalamic system or to the conveyance of thermal information.


Assuntos
Córtex Cerebral/fisiologia , Epilepsia/fisiopatologia , Nociceptividade/fisiologia , Dor/fisiopatologia , Percepção/fisiologia , Adulto , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Potenciais Somatossensoriais Evocados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurociências , Nociceptores/fisiologia , Dor/diagnóstico por imagem , Percepção da Dor/fisiologia , Percepção do Tato/fisiologia , Vibração
4.
Cell ; 181(2): 293-305.e11, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32142653

RESUMO

Pulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis (Mtb), manifests with a persistent cough as both a primary symptom and mechanism of transmission. The cough reflex can be triggered by nociceptive neurons innervating the lungs, and some bacteria produce neuron-targeting molecules. However, how pulmonary Mtb infection causes cough remains undefined, and whether Mtb produces a neuron-activating, cough-inducing molecule is unknown. Here, we show that an Mtb organic extract activates nociceptive neurons in vitro and identify the Mtb glycolipid sulfolipid-1 (SL-1) as the nociceptive molecule. Mtb organic extracts from mutants lacking SL-1 synthesis cannot activate neurons in vitro or induce cough in a guinea pig model. Finally, Mtb-infected guinea pigs cough in a manner dependent on SL-1 synthesis. Thus, we demonstrate a heretofore unknown molecular mechanism for cough induction by a virulent human pathogen via its production of a complex lipid.


Assuntos
Tosse/fisiopatologia , Glicolipídeos/metabolismo , Nociceptores/fisiologia , Fatores de Virulência/metabolismo , Adulto , Animais , Linhagem Celular , Tosse/etiologia , Tosse/microbiologia , Feminino , Glicolipídeos/fisiologia , Cobaias , Interações Hospedeiro-Patógeno , Humanos , Lipídeos/fisiologia , Pulmão/microbiologia , Macrófagos/microbiologia , Masculino , Camundongos , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/patogenicidade , Cultura Primária de Células , Tuberculose/microbiologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/fisiopatologia , Fatores de Virulência/fisiologia
5.
J Neurosci ; 40(11): 2189-2199, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32019828

RESUMO

The interaction between the immune system and the nervous system has been at the center of multiple research studies in recent years. Whereas the role played by cytokines as neuronal mediators is no longer contested, the mechanisms by which cytokines modulate pain processing remain to be elucidated. In this study, we have analyzed the involvement of granulocyte-macrophage colony stimulating factor (GM-CSF) in nociceptor activation in male and female mice. Previous studies have suggested GM-CSF might directly activate neurons. However, here we established the absence of a functional GM-CSF receptor in murine nociceptors, and suggest an indirect mechanism of action, via immune cells. We report that GM-CSF applied directly to magnetically purified nociceptors does not induce any transcriptional changes in nociceptive genes. In contrast, conditioned medium from GM-CSF-treated murine macrophages was able to drive nociceptor transcription. We also found that conditioned medium from nociceptors treated with the well established pain mediator, nerve growth factor, could also modify macrophage gene transcription, providing further evidence for a bidirectional crosstalk.SIGNIFICANCE STATEMENT The interaction of the immune system and the nervous system is known to play an important role in the development and maintenance of chronic pain disorders. Elucidating the mechanisms of these interactions is an important step toward understanding, and therefore treating, chronic pain disorders. This study provides evidence for a two-way crosstalk between macrophages and nociceptors in the peripheral nervous system, which may contribute to the sensitization of nociceptors by cytokines in pain development.


Assuntos
Dor Crônica/fisiopatologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Nociceptores/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Comunicação Celular , Células Cultivadas , Dor Crônica/induzido quimicamente , Meios de Cultivo Condicionados/farmacologia , Feminino , Gânglios Espinais/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/farmacologia , Nociceptores/fisiologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/efeitos dos fármacos , Fator de Transcrição STAT5/fisiologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Transcrição Genética/efeitos dos fármacos
6.
Proc Natl Acad Sci U S A ; 117(10): 5402-5408, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32102913

RESUMO

A distinct population of Foxp3+CD4+ regulatory T (Treg) cells promotes repair of acutely or chronically injured skeletal muscle. The accumulation of these cells depends critically on interleukin (IL)-33 produced by local mesenchymal stromal cells (mSCs). An intriguing physical association among muscle nerves, IL-33+ mSCs, and Tregs has been reported, and invites a deeper exploration of this cell triumvirate. Here we evidence a striking proximity between IL-33+ muscle mSCs and both large-fiber nerve bundles and small-fiber sensory neurons; report that muscle mSCs transcribe an array of genes encoding neuropeptides, neuropeptide receptors, and other nerve-related proteins; define muscle mSC subtypes that express both IL-33 and the receptor for the calcitonin-gene-related peptide (CGRP); and demonstrate that up- or down-tuning of CGRP signals augments or diminishes, respectively, IL-33 production by muscle mSCs and later accumulation of muscle Tregs. Indeed, a single injection of CGRP induced much of the genetic program elicited in mSCs early after acute skeletal muscle injury. These findings highlight neural/stromal/immune-cell crosstalk in tissue repair, suggesting future therapeutic approaches.


Assuntos
Células-Tronco Mesenquimais/fisiologia , Músculo Esquelético/lesões , Músculo Esquelético/fisiologia , Nociceptores/fisiologia , Regeneração , Linfócitos T Reguladores/imunologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Comunicação Celular , Interleucina-33/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos
7.
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
8.
Neurosci Bull ; 36(1): 1-10, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31230211

RESUMO

Topical irritants such as capsaicin (CAP), peppermint oil (PO), and mustard oil (MO) are effective in relieving inflammatory muscle pain. We investigated the effects of topical irritants in a rat model of inflammatory muscle pain produced by injecting complete Freund's adjuvant (CFA) into the tibialis anterior muscle. CFA-induced mechanical hypersensitivity and the spontaneous activity of muscular nociceptive afferents, and decreased weight-bearing of the hindlimb were relieved by topical application of CAP, PO, or MO on the skin overlying the inflamed muscle. The effects of topical irritants were abolished when applied to the skin on the ipsilateral plantar region or on the contralateral leg, or when the relevant cutaneous nerve or dorsal root was transected. Our results demonstrated that topical irritants may alleviate inflammatory muscle pain via activating cutaneous nociceptors and subsequently inhibiting the abnormal activity of muscular nociceptive neurons.


Assuntos
Mialgia/tratamento farmacológico , Mialgia/fisiopatologia , Neurônios Aferentes/fisiologia , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Pele/efeitos dos fármacos , Animais , Capsaicina , Feminino , Adjuvante de Freund/farmacologia , Hiperalgesia , Inflamação/induzido quimicamente , Irritantes , Modelos Animais , Mostardeira , Mialgia/induzido quimicamente , Dor Nociceptiva , Estimulação Física , Óleos Vegetais , Ratos , Ratos Sprague-Dawley
9.
Comp Med ; 69(6): 555-570, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31822322

RESUMO

Pain is a clinical syndrome arising from a variety of etiologies in a heterogeneous population, which makes successfully treating the individual patient difficult. Organizations and governments recognize the need for tailored and specific therapies, which drives pain research. This review summarizes the different types of pain assessments currently being used and the various rodent models that have been developed to recapitulate the human pain condition.


Assuntos
Modelos Animais de Doenças , Medição da Dor/métodos , Dor/fisiopatologia , Animais , Humanos , Camundongos , Nociceptores/fisiologia , Ratos
10.
Scand J Pain ; 20(1): 33-37, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31730538

RESUMO

Background Acute pain is a warning mechanism that exists to prevent tissue damage, however pain can outlast its protective purpose and persist beyond injury, becoming chronic. Chronic Pain is maladaptive and needs addressing as available medicines are only partially effective and cause severe side effects. There are profound differences between acute and chronic pain. Dramatic changes occur in both peripheral and central pathways resulting in the pain system being sensitised, thereby leading to exaggerated responses to noxious stimuli (hyperalgesia) and responses to non-noxious stimuli (allodynia). Critical role for immune system cells in chronic pain Preclinical models of neuropathic pain provide evidence for a critical mechanistic role for immune cells in the chronicity of pain. Importantly, human imaging studies are consistent with preclinical findings, with glial activation evident in the brain of patients experiencing chronic pain. Indeed, immune cells are no longer considered to be passive bystanders in the nervous system; a consensus is emerging that, through their communication with neurons, they can both propagate and maintain disease states, including neuropathic pain. The focus of this review is on the plastic changes that occur under neuropathic pain conditions at the site of nerve injury, the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. At these sites both endothelial damage and increased neuronal activity result in recruitment of monocytes/macrophages (peripherally) and activation of microglia (centrally), which release mediators that lead to sensitisation of neurons thereby enabling positive feedback that sustains chronic pain. Immune system reactions to peripheral nerve injuries At the site of peripheral nerve injury following chemotherapy treatment for cancer for example, the occurrence of endothelial activation results in recruitment of CX3C chemokine receptor 1 (CX3CR1)-expressing monocytes/macrophages, which sensitise nociceptive neurons through the release of reactive oxygen species (ROS) that activate transient receptor potential ankyrin 1 (TRPA1) channels to evoke a pain response. In the DRG, neuro-immune cross talk following peripheral nerve injury is accomplished through the release of extracellular vesicles by neurons, which are engulfed by nearby macrophages. These vesicles deliver several determinants including microRNAs (miRs), with the potential to afford long-term alterations in macrophages that impact pain mechanisms. On one hand the delivery of neuron-derived miR-21 to macrophages for example, polarises these cells towards a pro-inflammatory/pro-nociceptive phenotype; on the other hand, silencing miR-21 expression in sensory neurons prevents both development of neuropathic allodynia and recruitment of macrophages in the DRG. Immune system mechanisms in the central nervous system In the dorsal horn of the spinal cord, growing evidence over the last two decades has delineated signalling pathways that mediate neuron-microglia communication such as P2X4/BDNF/GABAA, P2X7/Cathepsin S/Fractalkine/CX3CR1, and CSF-1/CSF-1R/DAP12 pathway-dependent mechanisms. Conclusions and implications Definition of the modalities by which neuron and immune cells communicate at different locations of the pain pathway under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction and provides opportunities for novel approaches for the treatment of chronic pain.


Assuntos
Sistema Imunitário/inervação , Neuralgia/fisiopatologia , Nociceptores/fisiologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Animais , Receptor 1 de Quimiocina CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Gânglios Espinais/metabolismo , Humanos , Hiperalgesia , Microglia , Monócitos , Traumatismos dos Nervos Periféricos/metabolismo , Corno Dorsal da Medula Espinal/metabolismo
11.
Physiol Behav ; 212: 112695, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31647990

RESUMO

Spinal cord injury (SCI) is often accompanied by additional tissue damage (polytrauma) that provides a source of pain input. Our studies suggest that this pain input may be detrimental to long-term recovery. In a rodent model, we have shown that engaging pain (nociceptive) fibers caudal to a lower thoracic contusion SCI impairs recovery of locomotor function and increases tissue loss (secondary injury) and hemorrhage at the site of injury. In these studies, nociceptive fibers were activated using intermittent electrical stimulation. The stimulation parameters were derived from earlier studies demonstrating that 6 min of noxious stimulation, at an intensity (1.5 mA) that engages unmyelinated C (pain) fibers, induces a form of maladaptive plasticity within the lumbosacral spinal cord. We hypothesized that both shorter bouts of nociceptive input and lower intensities of stimulation will decrease locomotor function and increase spinal cord hemorrhage when rats have a spinal cord contusion. To test this, the present study exposed rats to electrical stimulation 24 h after a moderate lower thoracic contusion SCI. One group of rats received 1.5 mA stimulation for 0, 14.4, 72, or 180 s. Another group received six minutes of stimulation at 0, 0.17, 0.5, and 1.5 mA. Just 72 s of stimulation induced an acute disruption in motor performance, increased hemorrhage, and undermined the recovery of locomotor function. Likewise, less intense (0.5 mA) stimulation produced an acute disruption in motor performance, fueled hemorrhage, and impaired long-term recovery. The results imply that a brief period of moderate pain input can trigger hemorrhage after SCI and undermine long-term recovery. This highlights the importance of managing nociceptive signals after concurrent peripheral and central nervous system injuries.


Assuntos
Estimulação Elétrica/efeitos adversos , Hemorragia/fisiopatologia , Dor/fisiopatologia , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Hemorragia/complicações , Locomoção/fisiologia , Masculino , Nociceptores/fisiologia , Dor/complicações , Ratos , Traumatismos da Medula Espinal/complicações
12.
Nat Commun ; 10(1): 4253, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534133

RESUMO

Medication-overuse headaches (MOH) occur with both over-the-counter and pain-relief medicines, including paracetamol, opioids and combination analgesics. The mechanisms that lead to MOH are still uncertain. Here, we show that abnormal activation of Nav1.9 channels by Nitric Oxide (NO) is responsible for MOH induced by triptan migraine medicine. Deletion of the Scn11a gene in MOH mice abrogates NO-mediated symptoms, including cephalic and extracephalic allodynia, photophobia and phonophobia. NO strongly activates Nav1.9 in dural afferent neurons from MOH but not normal mice. Abnormal activation of Nav1.9 triggers CGRP secretion, causing artery dilatation and degranulation of mast cells. In turn, released mast cell mediators potentiates Nav1.9 in meningeal nociceptors, exacerbating inflammation and pain signal. Analysis of signaling networks indicates that PKA is downregulated in trigeminal neurons from MOH mice, relieving its inhibitory action on NO-Nav1.9 coupling. Thus, anomalous activation of Nav1.9 channels by NO, as a result of chronic medication, promotes MOH.


Assuntos
Transtornos da Cefaleia Secundários/patologia , Transtornos de Enxaqueca/patologia , Canal de Sódio Disparado por Voltagem NAV1.9/metabolismo , Neurônios Aferentes/metabolismo , Óxido Nítrico/metabolismo , Triptaminas/efeitos adversos , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Degranulação Celular/fisiologia , Células Cultivadas , Feminino , Transtornos da Cefaleia Secundários/induzido quimicamente , Hiperalgesia/fisiopatologia , Masculino , Mastócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Canal de Sódio Disparado por Voltagem NAV1.9/genética , Neurônios Aferentes/efeitos dos fármacos , Nociceptores/fisiologia , Dor/fisiopatologia , Uso Excessivo de Medicamentos Prescritos/efeitos adversos
13.
Cornea ; 38 Suppl 1: S11-S24, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31490785

RESUMO

Patients with corneal and conjunctival disorders report an array of ocular surface symptoms including stinging, foreign body sensation, and itching. The intensity and perceptual quality of these sensations and their duration, from brief intervals to long-term symptoms, also vary. We hypothesize that symptomatic differences across disorders reflect differences in the balance between ocular inflammation and nerve injury, with different conditions resulting from predominant effects of one of these, or a combined effect. This article provides an overview of corneal and conjunctival nerve cells, such as nociceptors and thermoreceptors, with descriptions of their morphological and molecular characteristics and their nerve-firing patterns and evoked sensations, as determined by earlier studies in animals and humans. Detailed descriptions of the changes in neuronal responses (such as abnormal responsiveness and spontaneous firing) due to local inflammation and nerve injury are provided, and assorted ocular surface disorders are discussed. Eye conditions in which inflammation is predominant include allergic conjunctivitis and photokeratitis, whereas nerve injury is the primary factor underlying complaints of dry eye after photorefractive keratectomy and in elderly patients. Both factors contribute substantially to dry eye disease and varicella-zoster infections. This model of the combined effects of inflammation and nerve injury serves to explain the different sensations reported in various eye surface disorders, including short-term versus chronic pain and dysesthesias, and may help to improve diagnoses and treatment methods.


Assuntos
Córnea/inervação , Síndromes do Olho Seco/diagnóstico , Dor Ocular/diagnóstico , Ceratite/diagnóstico , Nociceptores/fisiologia , Sensação/fisiologia , Termorreceptores/fisiopatologia , Síndromes do Olho Seco/fisiopatologia , Dor Ocular/etiologia , Humanos , Ceratite/fisiopatologia , Lágrimas/metabolismo
14.
Philos Trans R Soc Lond B Biol Sci ; 374(1785): 20190277, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31544606

RESUMO

Chronic pain is considered maladaptive by clinicians because it provides no apparent protective or recuperative benefits. Similarly, evolutionary speculations have assumed that chronic pain represents maladaptive or evolutionarily neutral dysregulation of acute pain mechanisms. By contrast, the present hypothesis proposes that chronic pain can be driven by mechanisms that evolved to reduce increased vulnerability to attack from predators and aggressive conspecifics, which often target prey showing physical impairment after severe injury. Ongoing pain and anxiety persisting long after severe injury continue to enhance vigilance and behavioural caution, decreasing the heightened vulnerability to attack that results from motor impairment and disfigurement, thereby increasing survival and reproduction (fitness). This hypothesis is supported by evidence of animals surviving and reproducing after traumatic amputations, and by complex specializations that enable primary nociceptors to detect local and systemic signs of injury and inflammation, and to maintain low-frequency discharge that can promote ongoing pain indefinitely. Ongoing activity in nociceptors involves intricate electrophysiological and anatomical specializations, including inducible alterations in the expression of ion channels and receptors that produce persistent hyperexcitability and hypersensitivity to chemical signals of injury. Clinically maladaptive chronic pain may sometimes result from the recruitment of this powerful evolutionary adaptation to severe bodily injury. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.


Assuntos
Evolução Biológica , Aptidão Genética , Nociceptores/fisiologia , Dor/fisiopatologia , Adaptação Fisiológica , Animais , Dor/etiologia
16.
Brain Res Bull ; 152: 299-310, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31377442

RESUMO

Visceral and somatic types of pain have been reported to manifest crucial differences not only in the experience, but also in their peripheral and central processing. However, the precise neuronal mechanisms that responsible for the modality-specific transmission of pain signals, especially at the supraspinal level, remain unclear. Very little is known also about the potential involvement of such mechanisms in the development of viscero-somatic hyperalgesia. Therefore, in the present study performed on urethane-anesthetized adult male Wistar rats we examined responses of neurons in the caudal ventrolateral medulla (CVLM)-the first site for supraspinal processing of both internal and external pain signals-to visceral (colorectal distension, CRD) and somatic (squeezing of the tail) noxious stimulations and evaluated alterations in response properties of these cells after the induction of colitis. It has been found out that the CVLM of healthy control rats, along with harboring of cells excited by both stimulations (23.7%), contained neurons that were activated by either visceral (31.9%) or somatic noxious stimuli (44.4%). In inflamed animals, the percentages of the visceral and somatic nociceptive cells were decreased (to 18.3% and 34.3%, correspondingly) and the number of bimodal neurons was increased (up to 47.4%); these alterations were associated with substantially enhanced responses of both the modality-specific and convergent CVLM neurons not only to CRD, but also to squeezing of the tail. Under these conditions, visceral and somatic pain stimuli induced similar changes in arterial blood pressure and respiratory rate, whereas in the absence of intestinal inflammation noxious CRD and tail stimulation evoked predominantly divergent autonomic reactions. The data obtained can benefit to a deeper understanding of the neuronal mechanisms that underlie differential supraspinal processing of visceral and somatic noxious stimuli and can potentially contribute to the realization of specific cardiovascular and respiratory accompaniments inherent to a particular type of pain. Therewith, results of the study elucidate colitis-induced alterations in these mechanisms, which may be responsible for the combined development of visceral hypersensitivity and somatic hyperalgesia.


Assuntos
Bulbo/metabolismo , Dor Nociceptiva/metabolismo , Dor Visceral/metabolismo , Animais , Tronco Encefálico/metabolismo , Colite/metabolismo , Colite/fisiopatologia , Inflamação/fisiopatologia , Masculino , Bulbo/fisiologia , Neurônios/fisiologia , Dor Nociceptiva/fisiopatologia , Nociceptores/fisiologia , Ratos , Ratos Wistar , Medula Espinal/fisiopatologia , Dor Visceral/fisiopatologia
17.
Neuroscience ; 417: 81-94, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31430528

RESUMO

Intrathecal (i.t.) administration of quinpirole, a dopamine (DA) D2-like receptor agonist, produces antinociception to mechanonociceptive stimuli but not to thermonociceptive stimuli. To determine a cellular mechanism for the specific antinociceptive effect of D2-like receptor activation on mechanonociception, we evaluated the effect of quinpirole on voltage-gated Ca2+ influx in cultured dorsal root ganglion (DRG) neurons and the D2 DA receptor distribution in subpopulations of rat nociceptive DRG neurons. Small-diameter DRG neurons were classified into IB4+ (nonpeptidergic) and IB4- (peptidergic). Intracellular [Ca2+] microfluorometry and voltage-clamp experiments showed that quinpirole reduced Ca2+ influx and inhibited the high voltage-activated Ca2+ current (HVA-ICa) in half of IB4+ neurons, leaving Ca2+ entry and HVA-ICa in IB4- neurons nearly unaffected. Pretreatment with ω-conotoxin MVIIA prevented the effect of quinpirole on HVA-ICa from IB4+ neurons, indicating that quinpirole mainly inhibits CaV2.2 channels. Immunofluorescence experiments showed that D2 DA receptor was present mainly in IB4+ small DRG neurons. Finally, in behavioral experiments in rats, the clinically approved D2-like receptor agonist pramipexole produced spinal antinociception in a similar fashion to quinpirole, with a significant effect only in the mechanonociceptive test. Our results explain, at least in part, why D2-like receptor agonists produce antinociception on mechanonociceptors.


Assuntos
Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Receptores de Dopamina D2/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Cálcio/metabolismo , Cálcio/fisiologia , Agonistas de Dopamina/farmacologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiologia , Masculino , Nociceptores/efeitos dos fármacos , Nociceptores/metabolismo , Nociceptores/fisiologia , Pramipexol/farmacologia , Quimpirol/farmacologia , Ratos , Ratos Wistar , Medula Espinal/metabolismo
18.
Science ; 365(6454): 695-699, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31416963

RESUMO

An essential prerequisite for the survival of an organism is the ability to detect and respond to aversive stimuli. Current belief is that noxious stimuli directly activate nociceptive sensory nerve endings in the skin. We discovered a specialized cutaneous glial cell type with extensive processes forming a mesh-like network in the subepidermal border of the skin that conveys noxious thermal and mechanical sensitivity. We demonstrate a direct excitatory functional connection to sensory neurons and provide evidence of a previously unknown organ that has an essential physiological role in sensing noxious stimuli. Thus, these glial cells, which are intimately associated with unmyelinated nociceptive nerves, are inherently mechanosensitive and transmit nociceptive information to the nerve.


Assuntos
Percepção da Dor/fisiologia , Células de Schwann/fisiologia , Pele/inervação , Animais , Feminino , Masculino , Mecanorreceptores/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Nociceptores/fisiologia , Optogenética , Limiar da Dor , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Células de Schwann/metabolismo , Termorreceptores/fisiologia
19.
Pain ; 160(10): 2305-2315, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31365468

RESUMO

Nerve growth factor (NGF) and its receptors TrkA and p75 play a key role in the development and function of peripheral nociceptive neurons. Here, we describe novel technology to selectively photoablate TrkA-positive nociceptors through delivery of a phototoxic agent coupled to an engineered NGF ligand and subsequent near-infrared illumination. We demonstrate that this approach allows for on demand and localized reversal of pain behaviors in mouse models of acute, inflammatory, neuropathic, and joint pain. To target peripheral nociceptors, we generated a SNAP-tagged NGF derivative NGF that binds to TrkA/p75 receptors but does not provoke signaling in TrkA-positive cells or elicit pain behaviors in mice. NGF was coupled to the photosensitizer IRDye700DX phthalocyanine (IR700) and injected subcutaneously. After near-infrared illumination of the injected area, behavioral responses to nociceptive mechanical and sustained thermal stimuli, but not innocuous stimuli, were substantially reduced. Similarly, in models of inflammatory, osteoarthritic, and neuropathic pain, mechanical hypersensitivity was abolished for 3 weeks after a single treatment regime. We demonstrate that this loss of pain behavior coincides with the retraction of neurons from the skin which then reinnervate the epidermis after 3 weeks corresponding with the return of mechanical hypersensitivity. Thus NGF-mediated photoablation is a minimally invasive approach to reversibly silence nociceptor input from the periphery, and control pain and hypersensitivity to mechanical stimuli.


Assuntos
Técnicas de Ablação/métodos , Fator de Crescimento Neural/administração & dosagem , Neuralgia/terapia , Nociceptores/efeitos dos fármacos , Medição da Dor/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Animais , Células CHO , Cricetinae , Cricetulus , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neuralgia/fisiopatologia , Nociceptores/fisiologia , Células PC12 , Ratos
20.
J Neurosci ; 39(36): 7061-7073, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31300521

RESUMO

Opioid-induced hyperalgesia (OIH) is a serious adverse event produced by opioid analgesics. Lack of an in vitro model has hindered study of its underlying mechanisms. Recent evidence has implicated a role of nociceptors in OIH. To investigate the cellular and molecular mechanisms of OIH in nociceptors, in vitro, subcutaneous administration of an analgesic dose of fentanyl (30 µg/kg, s.c.) was performed in vivo in male rats. Two days later, when fentanyl was administered intradermally (1 µg, i.d.), in the vicinity of peripheral nociceptor terminals, it produced mechanical hyperalgesia (OIH). Additionally, 2 d after systemic fentanyl, rats had also developed hyperalgesic priming (opioid-primed rats), long-lasting nociceptor neuroplasticity manifested as prolongation of prostaglandin E2 (PGE2) hyperalgesia. OIH was reversed, in vivo, by intrathecal administration of cordycepin, a protein translation inhibitor that reverses priming. When fentanyl (0.5 nm) was applied to dorsal root ganglion (DRG) neurons, cultured from opioid-primed rats, it induced a µ-opioid receptor (MOR)-dependent increase in [Ca2+]i in 26% of small-diameter neurons and significantly sensitized (decreased action potential rheobase) weakly IB4+ and IB4- neurons. This sensitizing effect of fentanyl was reversed in weakly IB4+ DRG neurons cultured from opioid-primed rats after in vivo treatment with cordycepin, to reverse of OIH. Thus, in vivo administration of fentanyl induces nociceptor neuroplasticity, which persists in culture, providing evidence for the role of nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of nociceptors, in OIH.SIGNIFICANCE STATEMENT Clinically used µ-opioid receptor agonists such as fentanyl can produce hyperalgesia and hyperalgesic priming. We report on an in vitro model of nociceptor neuroplasticity mediating this opioid-induced hyperalgesia (OIH) and priming induced by fentanyl. Using this model, we have found qualitative and quantitative differences between cultured nociceptors from opioid-naive and opioid-primed animals, and provide evidence for the important role of nociceptor µ-opioid receptor-mediated calcium signaling and peripheral protein translation in the weakly IB4-binding population of nociceptors in OIH. These findings provide information useful for the design of therapeutic strategies to alleviate OIH, a serious adverse event of opioid analgesics.


Assuntos
Analgésicos Opioides/toxicidade , Fentanila/toxicidade , Hiperalgesia/fisiopatologia , Plasticidade Neuronal , Nociceptores/efeitos dos fármacos , Potenciais de Ação , Animais , Sinalização do Cálcio , Gânglios Espinais/citologia , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Masculino , Nociceptores/metabolismo , Nociceptores/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides/metabolismo
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