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1.
Toxicol Lett ; 319: 74-84, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31707104

RESUMEN

Benzalkonium chloride (BAK), a quaternary ammonium compound widely used as disinfecting agent as well as preservative in eye drops is known to induce toxic effects on the ocular surface with inflammation and corneal nerve damage leading to dry eye disease (DED) in the medium-to-long term. The aim of this study was to evaluate in vitro the toxicity of a conditioned medium produced by corneal epithelial cells previously exposed to BAK (BAK-CM) on trigeminal neuronal cells. A human corneal epithelial (HCE) cell line was exposed to 5.10-3% BAK (i.e. 0.005% BAK) for 15 min and let recover for 5 h to prepare a BAK-CM. This BAK concentration is the lowest one found in eye drops. After this recovery period, BAK effect on HCE cells displayed cytotoxicity, morphological alteration, apoptosis, oxidative stress, ATP release, CCL2 and IL6 gene induction, as well as an increase in CCL2, IL-6 and MIF release. Next, a mouse trigeminal ganglion primary culture was exposed to the BAK-CM for 2 h, 4 h or 24 h. Whereas BAK-CM did not alter neuronal cell morphology, or induced neuronal cytotoxicity or oxidative stress, BAK-CM induced gene expression of Fos (neuronal activation marker), Atf3 (neuronal injury marker), Ccl2 and Il6 (inflammatory markers). Two and 4 h BAK-CM exposure promoted a neuronal damage (ATF-3, phospho-p38 increases; phospho-Stat3 decreases) while 24 h-BAK-CM exposure initiated a prosurvival pathway activation (phospho-p44/42, phospho-Akt increases; ATF-3, GADD153, active Caspase-3 decreases). In conclusion, this in vitro model, simulating paracrine mechanisms, represents an interesting tool to highlight the indirect toxic effects of BAK or any other xenobiotic on corneal trigeminal neurons and may help to better understand the cellular mechanisms that occur during DED pathophysiology.


Asunto(s)
Apoptosis/efectos de los fármacos , Compuestos de Benzalconio/toxicidad , Células Epiteliales/efectos de los fármacos , Epitelio Anterior/efectos de los fármacos , Inflamación/inducido químicamente , Neuronas/efectos de los fármacos , Conservadores Farmacéuticos/toxicidad , Ganglio del Trigémino/efectos de los fármacos , Factor de Transcripción Activador 3/biosíntesis , Factor de Transcripción Activador 3/efectos de los fármacos , Animales , Línea Celular , Síndromes de Ojo Seco/inducido químicamente , Síndromes de Ojo Seco/patología , Epitelio Anterior/citología , Expresión Génica/efectos de los fármacos , Humanos , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ganglio del Trigémino/citología
2.
J Headache Pain ; 20(1): 87, 2019 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-31375062

RESUMEN

BACKGROUND: Migraine is a debilitating neurological disorder involving abnormal trigeminovascular activation and sensitization. However, the underlying cellular and molecular mechanisms remain unclear. METHODS: A rat model of conscious migraine was established through the electrical stimulation (ES) of the dural mater surrounding the superior sagittal sinus. Using patch clamp recording, immunofluorescent labelling, enzyme-linked immunosorbent assays and western blot analysis, we studied the effects of ES on sensory neuronal excitability and elucidated the underlying mechanisms mediated by voltage-gated ion channels. RESULTS: The calcitonin gene-related peptide (CGRP) level in the jugular vein blood and the number of CGRP-positive neurons in the trigeminal ganglia (TGs) were significantly increased in rats with ES-induced migraine. The application of ES increased actional potential firing in both small-sized IB4-negative (IB4-) and IB4+ TG neurons. No significant changes in voltage-gated Na+ currents were observed in the ES-treated groups. ES robustly suppressed the transient outward K+ current (IA) in both types of TG neurons, while the delayed rectifier K+ current remained unchanged. Immunoblot analysis revealed that the protein expression of Kv4.3 was significantly decreased in the ES-treated groups, while Kv1.4 remained unaffected. Interestingly, ES increased the P/Q-type and T-type Ca2+ currents in small-sized IB4- TG neurons, while there were no significant changes in the IB4+ subpopulation of neurons. CONCLUSION: These results suggest that ES decreases the IA in small-sized TG neurons and increases P/Q- and T-type Ca2+ currents in the IB4- subpopulation of TG neurons, which might contribute to neuronal hyperexcitability in a rat model of ES-induced migraine.


Asunto(s)
Estimulación Eléctrica/métodos , Seno Sagital Superior/metabolismo , Ganglio del Trigémino/metabolismo , Potenciales de Acción , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Masculino , Neuronas Aferentes/fisiología , Ratas , Ratas Sprague-Dawley , Seno Sagital Superior/citología , Ganglio del Trigémino/citología
3.
J Oral Sci ; 61(1): 146-155, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30918211

RESUMEN

Bright light stimulation of the eye activates trigeminal subnucleus caudalis (Vc) neurons in rats. Sensory information is conveyed to the Vc via the trigeminal ganglion (TG). Thus, it is likely that TG neurons respond to photic stimulation and are involved in photic hypersensitivity. However, the mechanisms underlying this process are unclear. Therefore, the hypothesis in this study is bright light stimulation enhances the excitability of TG neurons involved in photic hypersensitivity. Expressions of calcitonin gene-related peptide (CGRP) and neuronal nitric oxide synthase (nNOS) were significantly higher in TG neurons from 5 min to 12 h after photic stimulation of the eye. Phosphorylation of extracellular signal-regulated kinase1/2 (pERK1/2) was enhanced in TG neurons within 5 min after photic stimulation, while pERK1/2 immunoreactivity in satellite glial cells (SGCs) persisted for more than 12 h after the stimulus. Activation of SGCs was observed from 5 min to 2 h. Expression of CGRP, nNOS, and pERK1/2 was observed in small and medium TG neurons, and activation of SGCs and pERK1/2-immunoreactive SGCs encircling large TG neurons was accelerated after stimulation. These results suggest that upregulation of CGRP, nNOS, and pERK1/2 within the TG is involved in photic hypersensitivity.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina/metabolismo , Ojo/efectos de la radiación , Luz , Sistema de Señalización de MAP Quinasas , Óxido Nítrico Sintasa de Tipo I/metabolismo , Ganglio del Trigémino/metabolismo , Regulación hacia Arriba , Animales , Ojo/enzimología , Ojo/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Masculino , Neuronas/metabolismo , Fosforilación , Ratas , Ratas Sprague-Dawley , Ganglio del Trigémino/citología , Ganglio del Trigémino/enzimología
4.
PLoS One ; 14(3): e0213866, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30921344

RESUMEN

Infectious laryngotracheitis (ILT) is a respiratory disease that affects chickens. It is caused by the alphaherpesvirus, infectious laryngotracheitis virus (ILTV). This virus undergoes lytic replication in the epithelial cells of the trachea and upper respiratory tract (URT) and establishes latent infection in the trigeminal ganglia (TG) and trachea. Live attenuated vaccines are widely used to control ILT. At least one of these vaccines can establish latent infections in chickens, but this has not been demonstrated for all vaccines. The aim of the current study was to determine the capacity of three commercially available vaccines (SA2, A20 and Serva) and a glycoprotein G deletion mutant vaccine candidate (ΔgG ILTV) to establish latent infection in the TG of specific pathogen free (SPF) chickens. Five groups of 7-day-old SPF chickens were eye-drop vaccinated with either one of the vaccine strains or mock-vaccinated with sterile media and followed until 20 or 21 days post-vaccination (dpv). ILTV DNA was detected at 20-21 dpv in the TG of 23/40 (57.5%) vaccinated SPF chickens (SA2 = 10/10; A20 = 6/10; Serva = 3/10; ΔgG = 4/10) by PCR, but virus could not be reactivated from TG co-cultivated with primary chicken embryo kidney cells. In the birds from which ILTV DNA was detected in the TG, ILTV DNA could not be detected in the URT or trachea of 3 birds in each of the SA2, A20 and Serva vaccinated groups, and in 4 birds in the ΔgG vaccinated group, indicating that these birds were latently infected in the absence of active lytic replication and virus shedding. Results from this study demonstrate the capacity of commercial ILTV vaccines to establish latent infections and underline their importance in the epidemiology of this disease.


Asunto(s)
Infecciones por Herpesviridae/prevención & control , Herpesvirus Gallináceo 1/inmunología , Enfermedades de las Aves de Corral/prevención & control , Ganglio del Trigémino/virología , Vacunas Atenuadas/inmunología , Animales , Pollos , ADN Viral/análisis , Infecciones por Herpesviridae/virología , Herpesvirus Gallináceo 1/genética , Soluciones Oftálmicas/química , Reacción en Cadena de la Polimerasa , Enfermedades de las Aves de Corral/virología , Sistema Respiratorio/virología , Organismos Libres de Patógenos Específicos , Tráquea/virología , Ganglio del Trigémino/citología , Vacunación/métodos , Vacunas Virales/inmunología
5.
Mar Drugs ; 17(3)2019 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-30841522

RESUMEN

Fucoxanthin is a carotenoid with many pharmaceutical properties that is found in brown seaweed. However, the effects of fucoxanthin on corneal innervation and intense eye pain have not been extensively examined. To clarify the protective roles and underlying mechanisms of fucoxanthin on ocular lesions, we investigated the beneficial effects and mechanisms by which fucoxanthin ameliorates ultraviolet B (UVB)-induced corneal denervation and trigeminal pain. Treatment with fucoxanthin enhanced the expression of nuclear factor erythroid 2-related factor 2 in the cornea. Inhibition of typical denervation and epithelial exfoliation in the cornea were observed in rats treated with fucoxanthin following UVB-induced nerve disorders. Moreover, the active phosphorylated form of p38 MAP kinase (pp38) and the number of glial fibrillary acidic protein (GFAP)-positive neural cells were significantly reduced. Decreased expression of neuron-selective transient receptor potential vanilloid type 1 (TRPV1) in the trigeminal ganglia neurons was also demonstrated in rats treated with fucoxanthin after UVB-induced keratitis. Symptoms of inflammatory pain, including difficulty in opening the eyes and eye wipe behaviour, were also reduced in fucoxanthin-treated groups. Pre-treatment with fucoxanthin may protect the eyes from denervation and inhibit trigeminal pain in UVB-induced photokeratitis models.


Asunto(s)
Dolor Ocular/tratamiento farmacológico , Queratitis/tratamiento farmacológico , Sustancias Protectoras/farmacología , Algas Marinas/química , Xantófilas/farmacología , Administración Oral , Animales , Córnea/efectos de los fármacos , Córnea/inervación , Córnea/efectos de la radiación , Desnervación , Modelos Animales de Enfermedad , Dolor Ocular/etiología , Humanos , Queratitis/etiología , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Sustancias Protectoras/uso terapéutico , Ratas , Ratas Sprague-Dawley , Canales Catiónicos TRPV/metabolismo , Ganglio del Trigémino/citología , Ganglio del Trigémino/efectos de los fármacos , Ganglio del Trigémino/metabolismo , Rayos Ultravioleta/efectos adversos , Xantófilas/uso terapéutico
6.
Mol Pain ; 15: 1744806919836570, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30784351

RESUMEN

Migraine is triggered by poor air quality and odors through unknown mechanisms. Activation of the trigeminovascular pathway by environmental irritants may occur via activation of transient receptor potential ankyrin 1 (TRPA1) receptors on nasal trigeminal neurons, but how that results in peripheral and central sensitization is unclear. The anatomy of the trigeminal ganglion suggests that noxious nasal stimuli are not being transduced to the meninges by axon reflex but likely through intraganglionic transmission. Consistent with this concept, we injected calcitonin gene-related peptide, adenosine triphosphate, or glutamate receptor antagonists or a gap junction channel blocker directly and exclusively into the trigeminal ganglion and blocked meningeal blood flow changes in response to acute nasal TRP agonists. Previously, we observed chronic sensitization of the trigeminovascular pathway after acrolein exposure, a known TRPA1 receptor agonist. To explore the mechanism of this sensitization, we utilized laser dissection microscopy to separately harvest nasal and meningeal trigeminal neuron populations in the absence or presence of acrolein exposure. mRNA levels of neurotransmitters important in migraine were then determined by reverse transcription polymerase chain reaction. TRPA1 message levels were significantly increased in meningeal cell populations following acrolein exposure compared to room air exposure. This was specific to TRPA1 message in meningeal cell populations as changes were not observed in either nasal trigeminal cell populations or dorsal root ganglion populations. Taken together, these data suggest an important role for intraganglionic transmission in acute activation of the trigeminovascular pathway. It also supports a role for upregulation of TRPA1 receptors in peripheral sensitization and a possible mechanism for chronification of migraine after environmental irritant exposure.


Asunto(s)
Ganglio del Trigémino/metabolismo , Acroleína/farmacología , Animales , Células Cultivadas , Electrofisiología , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Canal Catiónico TRPA1/agonistas , Canal Catiónico TRPA1/metabolismo , Ganglio del Trigémino/citología , Ganglio del Trigémino/efectos de los fármacos
7.
Int J Mol Sci ; 20(3)2019 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-30736422

RESUMEN

Neuron-glia interactions contribute to pain initiation and sustainment. Intra-ganglionic (IG) secretion of calcitonin gene-related peptide (CGRP) in the trigeminal ganglion (TG) modulates pain transmission through neuron-glia signaling, contributing to various orofacial pain conditions. The present study aimed to investigate the role of satellite glial cells (SGC) in TG in causing cytokine-related orofacial nociception in response to IG administration of CGRP. For that purpose, CGRP alone (10 µL of 10-5 M), Minocycline (5 µL containing 10 µg) followed by CGRP with one hour gap (Min + CGRP) were administered directly inside the TG in independent experiments. Rats were evaluated for thermal hyperalgesia at 6 and 24 h post-injection using an operant orofacial pain assessment device (OPAD) at three temperatures (37, 45 and 10 °C). Quantitative real-time PCR was performed to evaluate the mRNA expression of IL-1ß, IL-6, TNF-α, IL-1 receptor antagonist (IL-1RA), sodium channel 1.7 (NaV 1.7, for assessment of neuronal activation) and glial fibrillary acidic protein (GFAP, a marker of glial activation). The cytokines released in culture media from purified glial cells were evaluated using antibody cytokine array. IG CGRP caused heat hyperalgesia between 6⁻24 h (paired-t test, p < 0.05). Between 1 to 6 h the mRNA and protein expressions of GFAP was increased in parallel with an increase in the mRNA expression of pro-inflammatory cytokines IL-1ß and anti-inflammatory cytokine IL-1RA and NaV1.7 (one-way ANOVA followed by Dunnett's post hoc test, p < 0.05). To investigate whether glial inhibition is useful to prevent nociception symptoms, Minocycline (glial inhibitor) was administered IG 1 h before CGRP injection. Minocycline reversed CGRP-induced thermal nociception, glial activity, and down-regulated IL-1ß and IL-6 cytokines significantly at 6 h (t-test, p < 0.05). Purified glial cells in culture showed an increase in release of 20 cytokines after stimulation with CGRP. Our findings demonstrate that SGCs in the sensory ganglia contribute to the occurrence of pain via cytokine expression and that glial inhibition can effectively control the development of nociception.


Asunto(s)
Citocinas/metabolismo , Dolor Facial/metabolismo , Neuroglía/metabolismo , Nocicepción , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Ganglio del Trigémino/citología , Ganglio del Trigémino/metabolismo , Animales , Modelos Animales de Enfermedad , Dolor Facial/genética , Hiperalgesia/genética , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Masculino , Modelos Biológicos , Neuronas/metabolismo , Ratas , Temperatura Ambiental
8.
Glia ; 67(5): 791-801, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30715764

RESUMEN

Peripheral sensory ganglia contain the somata of neurons mediating mechanical, thermal, and painful sensations from somatic, visceral, and oro-facial organs. Each neuronal cell body is closely surrounded by satellite glial cells (SGCs) that have properties and functions similar to those of central astrocytes, including expression of gap junction proteins and functional dye coupling. As shown in other pain models, after systemic pain induction by intra-peritoneal injection of lipopolysaccharide, dye coupling among SGCs in intact trigeminal ganglion was enhanced. Moreover, neuron-neuron and neuron-SGC coupling was also detected. To verify the presence of gap junction-mediated coupling between SGCs and sensory neurons, we performed dual whole cell patch clamp recordings from both freshly isolated and short term cultured cell pairs dissociated from mouse trigeminal ganglia. Bidirectional gap junction mediated electrical responses were frequently recorded between SGCs, between neurons and between neurons and SGCs. Polarization of SGC altered neuronal excitability, providing evidence that gap junction-mediated interactions between neurons and glia within sensory ganglia may contribute to integration of peripheral sensory responses, and to the modulation and coordinaton of neuronal activity.


Asunto(s)
Uniones Comunicantes/fisiología , Neuroglía/fisiología , Neuronas/fisiología , Transmisión Sináptica/fisiología , Ganglio del Trigémino/citología , Animales , Compuestos de Boro/farmacología , Carbenoxolona/farmacología , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Ácido Flufenámico/farmacología , Uniones Comunicantes/efectos de los fármacos , Heptanol/farmacología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/patología , Isoquinolinas/metabolismo , Lipopolisacáridos/farmacología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Probenecid/farmacología , Transmisión Sináptica/efectos de los fármacos
9.
Int J Neurosci ; 129(8): 794-800, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-30636470

RESUMEN

Objective: The exact mechanism of phonophobia induced by subarachnoid hemorrhage (SAH) has not been understood well. This subject was investigated. Material and methods: This study was conducted on 25 rabbits. They divided into three groups: Five as control, five as SHAM, 20 as SAH group. All animals objected to 85 dB impulse noise by daily periods, and their phonophobic score values were examined by daily periods for 20 days. Their brains, trigeminal ganglia were extracted bilaterally. The normal and degenerated neuron densities of trigeminal ganglia were examined by stereological methods and compared with phonophobia scores. Results: Phonophobic score was 19-17, mean live neuron density (LND) of the trigeminal ganglia was 16.321 ± 2.430/mm3, and degenerated neuron density (DND) was 1.15 ± 0.120/mm3 in animals of control groups (n = 5). The phonophobic score was 17-14, LND: 14.345 ± 1.913/mm3, DND of the trigeminal ganglia was 1.150 ± 0.110/mm3 in SHAM group (n = 5). The phonophobic score was 14-8, LND: 12.987 ± 1.966/mm3, mean DND of the trigeminal ganglia was 2.520 ± 510/mm3 in animals with high phonophobia scores (n = 6). The phonophobic score was 7-4, LND: 9.122 ± 1.006, mean DND of the trigeminal ganglia was 5.820 ± 1.610/mm3, in animals with fever phonophobia scores (n = 9). Conclusion: An inverse relationship between DND trigeminal ganglion (TGG) and phonopobic score was found. The paralysis of tensor tympani muscle owing to trigeminal ganglia ischemia may be responsible for phonophobic clinical state in animals with SAH. In addition, there seems to be an important concern for the verbal component of GCS in SAH. These two important findings have not been published previously.


Asunto(s)
Hiperacusia , Hemorragia Subaracnoidea , Ganglio del Trigémino , Animales , Recuento de Células , Modelos Animales de Enfermedad , Hiperacusia/etiología , Hiperacusia/fisiopatología , Conejos , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/fisiopatología , Tensor del Tímpano/fisiopatología , Ganglio del Trigémino/citología , Ganglio del Trigémino/patología , Ganglio del Trigémino/fisiología
10.
Genesis ; 57(1): e23264, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30461190

RESUMEN

The cranial trigeminal ganglia play a vital role in the peripheral nervous system through their relay of sensory information from the vertebrate head to the brain. These ganglia are generated from the intermixing and coalescence of two distinct cell populations: cranial neural crest cells and placodal neurons. Trigeminal ganglion assembly requires the formation of cadherin-based adherens junctions within the neural crest cell and placodal neuron populations; however, the molecular composition of these adherens junctions is still unknown. Herein, we aimed to define the spatio-temporal expression pattern and function of Cadherin-7 during early chick trigeminal ganglion formation. Our data reveal that Cadherin-7 is expressed exclusively in migratory cranial neural crest cells and is absent from trigeminal neurons. Using molecular perturbation experiments, we demonstrate that modulation of Cadherin-7 in neural crest cells influences trigeminal ganglion assembly, including the organization of neural crest cells and placodal neurons within the ganglionic anlage. Moreover, alterations in Cadherin-7 levels lead to changes in the morphology of trigeminal neurons. Taken together, these findings provide additional insight into the role of cadherin-based adhesion in trigeminal ganglion formation, and, more broadly, the molecular mechanisms that orchestrate the cellular interactions essential for cranial gangliogenesis.


Asunto(s)
Proteínas Aviares/metabolismo , Cadherinas/metabolismo , Cresta Neural/metabolismo , Neuronas/metabolismo , Ganglio del Trigémino/metabolismo , Uniones Adherentes/metabolismo , Animales , Proteínas Aviares/genética , Cadherinas/genética , Embrión de Pollo , Cresta Neural/embriología , Neurogénesis , Ganglio del Trigémino/citología , Ganglio del Trigémino/embriología
11.
PLoS One ; 13(12): e0208089, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30517160

RESUMEN

Loss of one sensory modality can cause other types to become more perceptive (cross-modal plasticity). To test the hypothesis that the loss of vision changes the perceptual threshold in the somatosensory system, we applied optogenetics to directly manipulate the afferent inputs involved in the whisker-barrel system using a transgenic rat (W-TChR2V4) that expresses channelrhodopsin-2 (ChR2) selectively in the large mechanoreceptive neurons in the trigeminal ganglion (TG) and their peripheral nerve terminals. The licking behavior of W-TChR2V4 rat was conditioned to a blue LED light cue on the whisker area while the magnitude and duration of light pulses were varied. The perceptual threshold was thus quantitatively determined for each rat according to the relationship between the magnitude/duration of light and the reaction time between the LED light cue and the first licking event after it. We found that the perceptual threshold was more significantly reduced than the control non-deprived rats when the rats were visually deprived at postnatal 26-30 days (P26-30, early VD group), but not at P58-66 (late VD group). However, the sensory threshold of a late VD animal was similar to that of a control. Our results suggest the presence of cross-modal plasticity by which the loss of vision at the juvenile period increased the sensitivity of the somatosensory system involved in the touch of whiskers.


Asunto(s)
Plasticidad Neuronal/fisiología , Umbral Sensorial/fisiología , Corteza Somatosensorial/fisiología , Tacto/fisiología , Vibrisas/fisiología , Visión Ocular/fisiología , Animales , Femenino , Aseo Animal/fisiología , Luz , Masculino , Mecanorreceptores/citología , Mecanorreceptores/fisiología , Optogenética/métodos , Nervios Periféricos/citología , Nervios Periféricos/fisiología , Ratas , Ratas Transgénicas , Corteza Somatosensorial/citología , Factores de Tiempo , Ganglio del Trigémino/citología , Ganglio del Trigémino/fisiología , Vibrisas/citología
12.
Biol Aujourdhui ; 212(1-2): 1-11, 2018.
Artículo en Francés | MEDLINE | ID: mdl-30362450

RESUMEN

Dry eye disease (DED) is a common chronic condition with multifactorial etiologies that is increasing in prevalence worldwide, up to 20% in the elderly. The economic burden and impact of DED on vision, quality of life, work productivity, psychological and physical impact of pain, are considerable. Chronic ocular pain is the most common symptom of DED and there is currently no topical ocular analgesic therapy available to treat this debilitating disease. Eye pain can be perceived as itch, irritation, dryness, grittiness, burning, aching, and light sensitivity. Ocular pain is triggered by corneal nociceptors (cornea being the most sensory innervated tissue of the body). It was clearly established that repeated direct damage to ocular surface and per se corneal nerves can cause peripheral and central sensitization mechanisms explaining the ocular pain in some patients with DED. However, the brain regions and the neuronal pathways associated with ocular pain are still unclear. Thus, a better characterization of chronic ocular pain and an understanding of the peripheral and central molecular and cellular mechanisms involved are crucial issues for developing effective management and therapeutic strategy to alleviate ocular pain. In this review, we first describe the nociceptive corneal nerve pathways and the classification and the neurochemistry of primary afferents innervating the cornea. Then, an update of the fundamental and clinical studies related to the inflammatory processes linked to ocular pain is detailed. The last part of the review presents the diagnostic tools used in clinic for evaluating corneal sensitivity and corneal inflammation.


Asunto(s)
Dolor Crónico/etiología , Dolor Ocular/etiología , Dolor Crónico/patología , Comprensión , Córnea/anatomía & histología , Córnea/inervación , Córnea/patología , Síndromes de Ojo Seco/complicaciones , Síndromes de Ojo Seco/patología , Dolor Ocular/patología , Humanos , Neuronas Retinianas/citología , Neuronas Retinianas/patología , Neuronas Retinianas/fisiología , Ganglio del Trigémino/citología , Ganglio del Trigémino/patología , Ganglio del Trigémino/fisiología
13.
Eur J Pharmacol ; 841: 98-103, 2018 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-30336137

RESUMEN

Sumatriptan, a selective serotonin 5-HT1 receptor agonist, is an effective therapeutic for migraine attacks. However, the molecular mechanisms underlying sumatriptan migraine relief are still not fully understood. Here, we found that acid-sensing ion channels (ASICs), pH sensors, are peripheral targets of sumatriptan against migraine. Sumatriptan can inhibit the electrophysiological activity of ASICs in the trigeminal ganglion (TG) neurons. In the present study, sumatriptan decreased proton-gated currents mediated by ASICs in a concentration-dependent manner. In addition, sumatriptan shifted concentration-response curves for protons downwards, with a decrease of 37.3 ±â€¯4.6% in the maximum current response but with no significant change in the pH0.5 value. Sumatriptan inhibition of ASIC currents was blocked by 5-HT1D receptor antagonist BRL 15572, but not by 5-HT1B antagonist SB 224289. Moreover, the sumatriptan inhibition of ASICs can be mimicked by the 5-HT1D receptor agonist L-694,247, but not by the 5-HT1B agonist CP-93129. Sumatriptan inhibition of ASIC currents was also reversed by G-protein αi subunit inhibitor PTX and 8-Br-cAMP, suggesting the inhibition may involve the intracellular signal transduction. Finally, sumatriptan decreased the number of action potentials induced by acid stimuli in rat TG neurons. Our results indicated that the anti-migraine drug, sumatriptan, inhibited ASICs in rat TG neurons via 5-HT1D receptor subtype and a cAMP-dependent signal pathway. These observations add to the understanding of the mechanisms that underlie the clinical effectiveness of anti-migraine sumatriptan.


Asunto(s)
Canales Iónicos Sensibles al Ácido/metabolismo , Fenómenos Electrofisiológicos/efectos de los fármacos , Neuronas/citología , Neuronas/efectos de los fármacos , Sumatriptán/farmacología , Ganglio del Trigémino/citología , Potenciales de Acción/efectos de los fármacos , Animales , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Activación del Canal Iónico/efectos de los fármacos , Neuronas/metabolismo , Protones , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Ganglio del Trigémino/efectos de los fármacos
14.
Sci Rep ; 8(1): 13198, 2018 09 04.
Artículo en Inglés | MEDLINE | ID: mdl-30181551

RESUMEN

Sensory neurons innervating the dental pulp have unique morphological and functional characteristics compared to neurons innervating other tissues. Stimulation of dental pulp afferents whatever the modality or intensity of the stimulus, even light mechanical stimulation that would not activate nociceptors in other tissues, produces an intense pain. These specific sensory characteristics could involve receptors of the Transient Receptor Potential channels (TRP) family. In this study, we compared the expression of the cold sensitive receptors TRPM8 and TRPA1 in trigeminal ganglion neurons innervating the dental pulp, the skin of the cheek or the buccal mucosa and we evaluated the involvement of these receptors in dental pulp sensitivity to cold. We showed a similar expression of TRPM8, TRPA1 and CGRP in sensory neurons innervating the dental pulp, the skin or the mucosa. Moreover, we demonstrated that noxious cold stimulation of the tooth induced an overexpression of cFos in the trigeminal nucleus that was not prevented by the genetic deletion of TRPM8 or the administration of the TRPA1 antagonist HC030031. These data suggest that the unique sensory characteristics of the dental pulp are independent to TRPM8 and TRPA1 receptors expression and functionality.


Asunto(s)
Pulpa Dental/inervación , Células Receptoras Sensoriales/metabolismo , Canal Catiónico TRPA1/metabolismo , Canales Catiónicos TRPM/metabolismo , Sensación Térmica , Ganglio del Trigémino/citología , Animales , Células Cultivadas , Frío , Femenino , Masculino , Ratones Endogámicos C57BL , Células Receptoras Sensoriales/citología , Piel/inervación , Canal Catiónico TRPA1/análisis , Canales Catiónicos TRPM/análisis , Ganglio del Trigémino/metabolismo
15.
Proc Natl Acad Sci U S A ; 115(37): E8775-E8782, 2018 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-30154162

RESUMEN

Herpes simplex virus type 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Some HSE children carry inborn errors of the Toll-like receptor 3 (TLR3)-dependent IFN-α/ß- and -λ-inducing pathway. Induced pluripotent stem cell (iPSC)-derived cortical neurons with TLR3 pathway mutations are highly susceptible to HSV-1, due to impairment of cell-intrinsic TLR3-IFN immunity. In contrast, the contribution of cell-intrinsic immunity of human trigeminal ganglion (TG) neurons remains unclear. Here, we describe efficient in vitro derivation and purification of TG neurons from human iPSCs via a cranial placode intermediate. The resulting TG neurons are of sensory identity and exhibit robust responses to heat (capsaicin), cold (icilin), and inflammatory pain (ATP). Unlike control cortical neurons, both control and TLR3-deficient TG neurons were highly susceptible to HSV-1. However, pretreatment of control TG neurons with poly(I:C) induced the cells into an anti-HSV-1 state. Moreover, both control and TLR3-deficient TG neurons developed resistance to HSV-1 following pretreatment with IFN-ß but not IFN-λ. These data indicate that TG neurons are vulnerable to HSV-1 because they require preemptive stimulation of the TLR3 or IFN-α/ß receptors to induce antiviral immunity, whereas cortical neurons possess a TLR3-dependent constitutive resistance that is sufficient to block incoming HSV-1 in the absence of prior antiviral signals. The lack of constitutive resistance in TG neurons in vitro is consistent with their exploitation as a latent virus reservoir in vivo. Our results incriminate deficiencies in the constitutive TLR3-dependent response of cortical neurons in the pathogenesis of HSE.


Asunto(s)
Inmunidad/inmunología , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas/metabolismo , Receptor Toll-Like 3/metabolismo , Antivirales/farmacología , Diferenciación Celular/genética , Células Cultivadas , Corteza Cerebral/citología , Niño , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/fisiología , Humanos , Inmunidad/genética , Células Madre Pluripotentes Inducidas/citología , Interferón beta/farmacología , Mutación , Neuronas/efectos de los fármacos , Neuronas/virología , Poli I-C/farmacología , Receptor Toll-Like 3/genética , Ganglio del Trigémino/citología
16.
Nat Commun ; 9(1): 2041, 2018 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-29795268

RESUMEN

Innate behaviors are genetically encoded, but their underlying molecular mechanisms remain largely unknown. Predator odor 2,4,5-trimethyl-3-thiazoline (TMT) and its potent analog 2-methyl-2-thiazoline (2MT) are believed to activate specific odorant receptors to elicit innate fear/defensive behaviors in naive mice. Here, we conduct a large-scale recessive genetics screen of ethylnitrosourea (ENU)-mutagenized mice. We find that loss of Trpa1, a pungency/irritancy receptor, diminishes TMT/2MT and snake skin-evoked innate fear/defensive responses. Accordingly, Trpa1 -/- mice fail to effectively activate known fear/stress brain centers upon 2MT exposure, despite their apparent ability to smell and learn to fear 2MT. Moreover, Trpa1 acts as a chemosensor for 2MT/TMT and Trpa1-expressing trigeminal ganglion neurons contribute critically to 2MT-evoked freezing. Our results indicate that Trpa1-mediated nociception plays a crucial role in predator odor-evoked innate fear/defensive behaviors. The work establishes the first forward genetics screen to uncover the molecular mechanism of innate fear, a basic emotion and evolutionarily conserved survival mechanism.


Asunto(s)
Conducta Animal/fisiología , Miedo/fisiología , Instinto , Olfato/fisiología , Canal Catiónico TRPA1/fisiología , Animales , Femenino , Técnicas de Genotipaje , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutagénesis , Neuronas/fisiología , Nocicepción/fisiología , Odorantes , Tiazoles/química , Ganglio del Trigémino/citología , Ganglio del Trigémino/fisiología
17.
J Endod ; 44(6): 984-991.e2, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29709295

RESUMEN

INTRODUCTION: Various stimuli to the dentin surface elicit dentinal pain by inducing dentinal fluid movement causing cellular deformation in odontoblasts. Although odontoblasts detect deformation by the activation of mechanosensitive ionic channels, it is still unclear whether odontoblasts are capable of establishing neurotransmission with myelinated A delta (Aδ) neurons. Additionally, it is still unclear whether these neurons evoke action potentials by neurotransmitters from odontoblasts to mediate sensory transduction in dentin. Thus, we investigated evoked inward currents and evoked action potentials form trigeminal ganglion (TG) neurons after odontoblast mechanical stimulation. METHODS: We used patch clamp recordings to identify electrophysiological properties and record evoked responses in TG neurons. RESULTS: We classified TG cells into small-sized and medium-sized neurons. In both types of neurons, we observed voltage-dependent inward currents. The currents from medium-sized neurons showed fast inactivation kinetics. When mechanical stimuli were applied to odontoblasts, evoked inward currents were recorded from medium-sized neurons. Antagonists for the ionotropic adenosine triphosphate receptor (P2X3), transient receptor potential channel subfamilies, and Piezo1 channel significantly inhibited these inward currents. Mechanical stimulation to odontoblasts also generated action potentials in the isolectin B4-negative medium-sized neurons. Action potentials in these isolectin B4-negative medium-sized neurons showed a short duration. Overall, electrophysiological properties of neurons indicate that the TG neurons with recorded evoked responses after odontoblast mechanical stimulation were myelinated Aδ neurons. CONCLUSIONS: Odontoblasts established neurotransmission with myelinated Aδ neurons via P2X3 receptor activation. The results also indicated that mechanosensitive TRP/Piezo1 channels were functionally expressed in odontoblasts. The activation of P2X3 receptors induced an action potential in the Aδ neurons, underlying a sensory generation mechanism of dentinal pain.


Asunto(s)
Potenciales de Acción/fisiología , Mecanorreceptores/fisiología , Odontoblastos/fisiología , Canales Receptores Transitorios de Potencial/fisiología , Ganglio del Trigémino/citología , Animales , Técnicas de Cocultivo/métodos , Femenino , Masculino , Proteínas de la Membrana/fisiología , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Ganglio del Trigémino/fisiología
18.
Endocrinology ; 159(5): 2253-2263, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29648633

RESUMEN

Previous studies have implicated urotensin-II in the nociception of sensory neurons. However, to date the relevant mechanisms remain unknown. In the current study we determined the role of urotensin-II in the regulation of transient outward A-type potassium currents (IA) and neuronal excitability in trigeminal ganglion (TG) neurons. We found that application of urotensin-II to small-diameter TG neurons decreased IA in a dose-dependent manner, whereas the delayed rectifier potassium current was unaffected. The IA decrease induced by urotensin-II depended on the urotensin-II receptor (UT-R) and was associated with a hyperpolarizing shift in the steady-state inactivation curve. Exposure of TG cells to urotensin-II markedly increased protein kinase C (PKC) activity, and PKC inhibition eliminated the UT-R-mediated IA decrease. Antagonism of PKCα, either pharmacologically or genetically, but not of PKCß prevented the decrease in IA induced by urotensin-II. Analysis of phospho-extracellular signal-regulated kinase (p-ERK) revealed that urotensin-II significantly increased the expression level of p-ERK, whereas p-p38 and p-c-Jun N-terminal kinase remained unchanged. Inhibition of mitogen-activated protein kinase/ERK signaling by the kinase antagonist U0126 and PD98059 completely abolished the UT-R-mediated IA decrease. Moreover, urotensin-II significantly increased the action potential firing rate of small TG neurons; pretreatment with 4-aminopyridine prevented this effect. In summary, our findings suggest that urotensin-II selectively attenuated IA through stimulation of the PKCα-dependent ERK1/2 signaling pathway. This UT-R-dependent mechanism might contribute to neuronal hyperexcitability in TG neurons.


Asunto(s)
Potenciales de Acción/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Canales de Potasio con Entrada de Voltaje/efectos de los fármacos , Proteína Quinasa C-alfa/efectos de los fármacos , Células Receptoras Sensoriales/efectos de los fármacos , Ganglio del Trigémino/citología , Urotensinas/farmacología , 4-Aminopiridina/farmacología , Animales , Expresión Génica/efectos de los fármacos , Ratones , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio con Entrada de Voltaje/metabolismo , Proteína Quinasa C-alfa/metabolismo , Transducción de Señal
19.
Brain Res ; 1690: 31-39, 2018 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-29649466

RESUMEN

Transient receptor potential ankyrin 1 (TRPA1), a cold receptor in sensory neurons activated by a variety of stimuli, is implicated in nociception and mechanotransduction. To help understand the vesicular glutamate transporter (VGLUT)-mediated glutamate signaling in TRPA1-immunopositive (+) neurons, we examined the expression of VGLUT1 and VGLUT2 in the TRPA1+ neurons in the male rat trigeminal ganglion (n = 19) under normal conditions and following experimental inflammation in the vibrissal pad by light microscopic immunohistochemistry (n = 11), western blot (n = 8), and quantitative analysis. One half (50.8%, 250/492) of the TRPA1+ neurons expressed VGLUT2, and a small fraction (8.3%, 57/683) also expressed VGLUT1. The majority of the VGLUT2-expressing TRPA1+ (VGLUT2+/TRPA1+) neurons coexpressed the markers of peptidergic and non-peptidergic neurons, CGRP, IB4, and TRPV1 but not the markers of neurons with myelinated fibers, NF200 and parvalbumin. In contrast, most VGLUT1+/TRPA1+ neurons coexpressed NF200 and parvalbumin but rarely expressed CGRP, IB4, or TRPV1. Following experimental inflammation, the fraction of VGLUT2+ (experimental vs. control: 34.7% vs. 22.3%), TRPA1+ (39.3% vs. 25.3%), and VGLUT2+/TRPA1+ (60.7% vs. 49.7%) neurons and the protein levels for TRPA1 and VGLUT2 increased significantly, compared to control, whereas the fraction of VGLUT1+ and VGLUT1+/TRPA1+ neurons and the protein level for VGLUT1 remained unchanged. These findings suggest that both VGLUT1 and VGLUT2 are involved in the glutamate signaling in TRPA1+ neurons under normal conditions in the male rats, and raise a possibility that VGLUT2 may play a role in the TRPA1-induced hypersensitivity following inflammation.


Asunto(s)
Neuronas/metabolismo , Canal Catiónico TRPA1/metabolismo , Ganglio del Trigémino/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo , Animales , Inflamación/metabolismo , Inflamación/patología , Masculino , Neuronas/citología , Neuronas/patología , Ratas Sprague-Dawley , Ganglio del Trigémino/citología , Ganglio del Trigémino/patología , Regulación hacia Arriba , Vibrisas
20.
J Mol Histol ; 49(3): 257-263, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29516260

RESUMEN

Satellite glial cells (SGCs), a peripheral neuroglial cell, surround neurons and form a complete envelope around individual sensory neurons in the trigeminal ganglia (TG), which may be involved in modulating neurons in inflammation. The purpose of this study was to determine the effect of dental injury and inflammation on SGCs in the TG. Pulp exposure (PX) was performed on the first maxillary molar of 28 rats. The neurons innervating injured tooth in TG were labeled by the retrograde transport of fluoro-gold (FG). Specimens were collected at 1, 3, 7, 14, 21 and 28 days after PX and stained immunohistochemically for glial fibrillary acid protein (GFAP), a marker of SGCs activation, in the TG. We observed that GFAP-immunoreactivity (IR) SGCs enclosed FG-labeled neurons increased in a time-dependent manner after PX. The neurons surrounded by GFAP-IR SGCs were mainly small and medium in size. The GFAP-IR SGCs encircled neurons increased significantly in the maxillary nerve region of the TG at 7-28 days following PX. The results show that dental injury and inflammation induced SGCs activation in the TG. It indicates that activation of SGCs might be implicated in the peripheral mechanisms of pain following dental injury and inflammation.


Asunto(s)
Inflamación/etiología , Neuroglía/metabolismo , Células Satélites Perineuronales/metabolismo , Traumatismos de los Dientes/patología , Ganglio del Trigémino/citología , Animales , Proteína Ácida Fibrilar de la Glía/análisis , Nervio Maxilar/citología , Neuronas/metabolismo , Dolor/etiología , Ratas , Factores de Tiempo
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