RESUMO
Depression symptoms are often found in patients suffering from chronic pain, a phenomenon that is yet to be understood mechanistically. Here, we systematically investigate the cellular mechanisms and circuits underlying the chronic-pain-induced depression behavior. We show that the development of chronic pain is accompanied by depressive-like behaviors in a mouse model of trigeminal neuralgia. In parallel, we observe increased activity of the dopaminergic (DA) neuron in the midbrain ventral tegmental area (VTA), and inhibition of this elevated VTA DA neuron activity reverses the behavioral manifestations of depression. Further studies establish a pathway of glutamatergic projections from the spinal trigeminal subnucleus caudalis (Sp5C) to the lateral parabrachial nucleus (LPBN) and then to the VTA. These glutamatergic projections form a direct circuit that controls the development of the depression-like behavior under the state of the chronic neuropathic pain.
Assuntos
Comportamento Animal , Dor Crônica/fisiopatologia , Depressão/fisiopatologia , Núcleos Parabraquiais/fisiopatologia , Neuralgia do Trigêmeo/fisiopatologia , Área Tegmentar Ventral/fisiopatologia , Potenciais de Ação , Animais , Dor Crônica/metabolismo , Dor Crônica/psicologia , Depressão/metabolismo , Depressão/psicologia , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Núcleos Parabraquiais/metabolismo , Núcleo Inferior Caudal do Nervo Trigêmeo/metabolismo , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologia , Neuralgia do Trigêmeo/metabolismo , Neuralgia do Trigêmeo/psicologia , Área Tegmentar Ventral/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/genética , Proteína Vesicular 2 de Transporte de Glutamato/metabolismoRESUMO
Peripheral inflammation induces plastic changes in neurons and glia which are regulated by free calcium and calcium binding proteins (CaBP). One of the mechanisms associated with the regulation of intracellular calcium is linked to ERK (Extracellular Signal-Regulated Kinase) and its phosphorylated condition (pERK). ERK phosphorylation is important for intracellular signal transduction and participates in regulating neuroplasticity and inflammatory responses. The aim of this study is to analyse the expression of two CaBPs and pERK in astrocytes and neurons in rat trigeminal subnucleus caudalis (Vc) after experimental periapical inflammation on the left mandibular first molar. At seven days post-treatment, the periapical inflammatory stimulus induces an increase in pERK expression both in S100b positive astrocytes and Calbindin D28k positive neurons, in the ipsilateral Vc with respect to the contralateral side and control group. pERK was observed coexpressing with S100b in astrocytes and in fusiform Calbindin D28k neurons in lamina I. These results could indicate that neural plasticity and pain sensitization could be maintained by ERK activation in projection neurons at 7 days after the periapical inflammation.
La inflamación periférica induce cambios plásticos en las neuronas y en la glía, los cuales están regulados por el calcio libre y las proteínas fijadoras calcio (CaBP). Uno de los mecanismos asociados con la regulación del calcio intrace-lular está vinculado con la fosforilación de la pro teína quinasa ERK. Asimismo, ERK fosforilado es importante para la trans-ducción de señales intracelulares y participa en la regulación de la neuroplasticidad y las respuestas inflamatorias. El objetivo de este estudio es analizar la expresión de dos CaBPs y pERK en astrocitos y neuronas del subnúcleo caudal del trigémino (Vc) después de una inflamación periapical experimental en el primer molar inferior izquierdo en ratas. A los siete días posteriores al tratamiento, el estímulo inflamatorio periapical induce un aumento en la expresión de pERK, en el número de astrocitos positivos para la proteína marcadora astroglial S100b y en neuronas positivas para Calbindina D28k, en el Vc ipsilateral respecto del lado contralateral y el grupo de control. Además, se observó coexpresión de pERK tanto en astrocitos S100b positivos, como en neuronas fusiformes Calbindin D28k positivas, de la lámina I. Estas observaciones podrían indicar que la neuroplasticidad y la sensibilización al dolor podrían mantenerse mediante la activación de ERK en las neuronas de proyección a los 7 días de la inflamación periapical.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inflamação , Plasticidade Neuronal , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologia , Animais , Astrócitos/metabolismo , Astrócitos/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Núcleos do TrigêmeoRESUMO
Peripheral inflammation induces plastic changes in neurons and glia which are regulated by free calcium and calcium binding proteins (CaBP). One of the mechanisms associated with the regulation of intracellular calcium is linked to ERK (Extracellular Signal-Regulated Kinase) and its phosphorylated condition (pERK). ERK phosphorylation is important for intracellular signal transduction and participates in regulating neuroplasticity and inflammatory responses. The aim of this study is to analyse the expression of two CaBPs and pERK in astrocytes and neurons in rat trigeminal subnucleus caudalis (Vc) after experimental periapical inflammation on the left mandibular first molar. At seven days post-treatment, the periapical inflammatory stimulus induces an increase in pERK expression both in S100b positive astrocytes and Calbindin D28k positive neurons, in the ipsilateral Vc with respect to the contralateral side and control group. pERK was observed coexpressing with S100b in astrocytes and in fusiform Calbindin D28k neurons in lamina I. These results could indicate that neural plasticity and pain sensitization could be maintained by ERK activation in projection neurons at 7 days after the periapical inflammation.
La inflamación periférica induce cambios plásticos en las neuronas y en la glía, los cuales están regulados por el calcio libre y las proteínas fijadoras calcio (CaBP). Uno de los mecanismos asociados con la regulación del calcio intrace-lular está vinculado con la fosforilación de la pro teína quinasa ERK. Asimismo, ERK fosforilado es importante para la trans-ducción de señales intracelulares y participa en la regulación de la neuroplasticidad y las respuestas inflamatorias. El objetivo de este estudio es analizar la expresión de dos CaBPs y pERK en astrocitos y neuronas del subnúcleo caudal del trigémino (Vc) después de una inflamación periapical experimental en el primer molar inferior izquierdo en ratas. A los siete días posteriores al tratamiento, el estímulo inflamatorio periapical induce un aumento en la expresión de pERK, en el número de astrocitos positivos para la proteína marcadora astroglial S100b y en neuronas positivas para Calbindina D28k, en el Vc ipsilateral respecto del lado contralateral y el grupo de control. Además, se observó coexpresión de pERK tanto en astrocitos S100b positivos, como en neuronas fusiformes Calbindin D28k positivas, de la lámina I. Estas observaciones podrían indicar que la neuroplasticidad y la sensibilización al dolor podrían mantenerse mediante la activación de ERK en las neuronas de proyección a los 7 días de la inflamación periapical.
Assuntos
Animais , Ratos , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologia , Proteínas de Ligação ao Cálcio/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inflamação , Plasticidade Neuronal , Núcleos do Trigêmeo , Astrócitos/fisiologia , Astrócitos/metabolismo , Ratos Sprague-Dawley , Neurônios/fisiologia , Neurônios/metabolismoRESUMO
BACKGROUND: Migraine is a highly prevalent, disabling, and costly disorder worldwide. From a long time ago, headaches have been known to be associated with gastrointestinal (GI) disorders. Headaches originating from gastric complaints were appreciated by Persian Medicine (PM) scholars. Today, functional GI disorders are shown to have high comorbidity with migraines; however, a causal relationship is not accepted today and pathophysiological explanations for this comorbidity are scarce. Therefore, based on the PM philosophy and the existing evidence, we aimed to propose an explanation for the co-morbidity of migraine and GI disorders. SUMMARY: Noxious stimuli from the GI tract are relayed to the nucleus tractus solitarius (NTS) in the brain stem, which is located close to the trigeminal nucleus caudalis (TNC). TNC has shown projections to (NTS) through which frequent GI stimuli may antidromically reach the TNC and finally result in neurogenic inflammation. In addition, immune products, particularly histamine, are released in the submucosa of the GI tract and absorbed into the systemic circulation, which renders migraineurs more prone to attacks.
Assuntos
Gastroenteropatias/complicações , Transtornos de Enxaqueca/complicações , Tronco Encefálico/fisiopatologia , Comorbidade , Gastroenteropatias/fisiopatologia , Cefaleia/complicações , Histamina/química , Humanos , Inflamação , Transtornos de Enxaqueca/fisiopatologia , Modelos Biológicos , Resultado do Tratamento , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologiaRESUMO
Most previous studies suggest that the subnucleus caudalis (Vc) of spinal trigeminal nucleus (Vsp) plays a key role in the generation and maintenance of migraine, a type of primary headache, by participating in the trigeminovascular system. Furthermore, the excitability of the Vc with the stimulation of the peripheral nociceptive fibers innervating the intracranial vessels or dura matter is regarded as a main cellular substrate for migraine. Here, a revised hypothesis is introduced, reinforcing the previous hypothesis and complementing it. This hypothesis suggests that, besides the Vc, much broader areas of the trigeminal sensory nuclei (Vsn), i.e., the principal sensory nucleus (Vp), the oralis nucleus (Vo), and the interpolaris nucleus (Vi), contribute to process and integrate pain signals generated in the head. In addition, the plasticity of synaptic transmission between nuclei or subnuclei in the Vsn, in particular, the Vsp, can be a cellular model for migraine, in the same way as the hippocampal synaptic plasticity is a model for learning and memory. This hypothesis will contribute to the discovery of new therapeutic tools for patients with migraine.
Assuntos
Potenciação de Longa Duração/fisiologia , Transtornos de Enxaqueca/etiologia , Núcleo Espinal do Trigêmeo/fisiopatologia , Animais , Humanos , Potenciação de Longa Duração/genética , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/fisiopatologia , Modelos Neurológicos , Mutação , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Receptores de Serotonina/fisiologia , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologiaRESUMO
Background The blood-brain barrier (BBB) has been hypothesized to play a role in migraine since the late 1970s. Despite this, limited investigation of the BBB in migraine has been conducted. We used the inflammatory soup rat model of trigeminal allodynia, which closely mimics chronic migraine, to determine the impact of repeated dural inflammatory stimulation on BBB permeability. Methods The sodium fluorescein BBB permeability assay was used in multiple brain regions (trigeminal nucleus caudalis (TNC), periaqueductal grey, frontal cortex, sub-cortex, and cortex directly below the area of dural activation) during the episodic and chronic stages of repeated inflammatory dural stimulation. Glial activation was assessed in the TNC via GFAP and OX42 immunoreactivity. Minocycline was tested for its ability to prevent BBB disruption and trigeminal sensitivity. Results No astrocyte or microglial activation was found during the episodic stage, but BBB permeability and trigeminal sensitivity were increased. Astrocyte and microglial activation, BBB permeability, and trigeminal sensitivity were increased during the chronic stage. These changes were only found in the TNC. Minocycline treatment prevented BBB permeability modulation and trigeminal sensitivity during the episodic and chronic stages. Discussion Modulation of BBB permeability occurs centrally within the TNC following repeated dural inflammatory stimulation and may play a role in migraine.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Mediadores da Inflamação/toxicidade , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologia , Neuralgia do Trigêmeo/fisiopatologia , Animais , Barreira Hematoencefálica/patologia , Modelos Animais de Doenças , Dura-Máter/efeitos dos fármacos , Dura-Máter/patologia , Inflamação/induzido quimicamente , Masculino , Transtornos de Enxaqueca/fisiopatologia , Ratos , Ratos Sprague-Dawley , Núcleo Inferior Caudal do Nervo Trigêmeo/efeitos dos fármacosRESUMO
Introduction Research in development of new migraine therapeutics is hindered by the lack of suitable, predictive animal models. Cilostazol provokes headache in healthy humans and migraineurs by increasing intracellular cAMP levels. We aimed to investigate whether cilostazol could provoke headache-like behaviours and c-fos expression in rats. In order to evaluate the predictive validity of the model, we examined the response to the migraine specific drug sumatriptan. Methods The effect of cilostazol (125 mg/kg p.o.) in female Sprague Dawley rats was evaluated on a range of spontaneous behavioural parameters, light sensitivity and mechanical sensitivity thresholds. We also measured c-fos expression in the trigeminal nucleus caudalis. Results Cilostazol increased light sensitivity and grooming behaviour. These manifestations were not inhibited by sumatriptan. Cilostazol also induced c-fos expression in the trigeminal nucleus caudalis. Furthermore, trigeminal - but not hind paw hyperalgesia was observed. Conclusion The altered behaviours are suggestive of cilostazol induced headache with migraine-like features, but not specific. The presence of head specific hyperalgesia and the c-fos response in the trigeminal nucleus caudalis imply that the model involves trigeminal nociception. The model will be useful for studying mechanisms related to the cAMP pathway in headache, but its predictive properties appear to be more limited due to the lack of response to sumatriptan.
Assuntos
Cilostazol/toxicidade , Transtornos de Enxaqueca/induzido quimicamente , Proteínas Proto-Oncogênicas c-fos/biossíntese , Núcleo Inferior Caudal do Nervo Trigêmeo/efeitos dos fármacos , Vasodilatadores/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Transtornos de Enxaqueca/metabolismo , Transtornos de Enxaqueca/fisiopatologia , Ratos , Ratos Sprague-Dawley , Núcleo Inferior Caudal do Nervo Trigêmeo/metabolismo , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologiaRESUMO
We investigated the effect of botulinum neurotoxin type A (BoNT-A) on mechanical allodynia and hyperalgesia associated with infraorbital nerve constriction (ION-CCI) in rats. ION-CCI rats received a subcutaneous BoNT-A injection into the whisker pad area on day 7 postoperatively and underwent pain assessment on days 14 and 21 postoperatively. Rats were assigned to one of four treatment groups (n=5 each): ION-CCI+BoNT-A 20pg (low-dose group), ION-CCI+BoNT-A 200pg (high-dose group), ION-CCI+saline, and Sham. Mechanical allodynia and hyperalgesia were evaluated preoperatively (baseline) and on days 7, 14, and 21 postoperatively. After noxious mechanical stimulation of whisker pad skin, the number and distribution pattern of the phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive (IR) neurons were analyzed in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2). On day 21, nocifensive behavior was attenuated by high-dose but not low-dose BoNT-A administration. In addition, after noxious mechanical stimulation of whisker pad skin, the numbers of pERK-IR cells in the superficial laminae of Vc and C1-C2 were significantly lower in the high-dose BoNT-A group than in the ION-CCI+saline group. The present findings suggest that, by suppressing Vc neuronal activity, high-dose intradermal injection of BoNT-A at the site of ION innervation alleviates mechanical facial allodynia and hyperalgesia associated with ION-CCI.
Assuntos
Toxinas Botulínicas Tipo A/farmacologia , Hiperalgesia/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Medula Espinal/metabolismo , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologia , Animais , Vértebras Cervicais/fisiopatologia , Constrição , Masculino , Medição da Dor , Ratos Sprague-Dawley , TatoRESUMO
Although a modulatory role has been reported for the red wine polyphenol resveratrol on several types of ion channels and excitatory synaptic transmission in the nervous system, the acute effects of resveratrol in vivo, particularly on nociceptive transmission of the trigeminal system, remain to be determined. The aim of the present study was to investigate whether acute intravenous resveratrol administration to rats attenuates the excitability of wide dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. Extracellular single unit recordings were made from 18 SpVc neurons in response to orofacial mechanical stimulation of pentobarbital-anesthetized rats. Responses to both non-noxious and noxious mechanical stimuli were analyzed in the present study. The mean firing frequency of SpVc WDR neurons in response to both non-noxious and noxious mechanical stimuli was inhibited by resveratrol (0.5-2 mg/kg, i.v.) and maximum inhibition of the discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 10 min. These inhibitory effects were reversed after approximately 20 min. The relative magnitude of inhibition by resveratrol of SpVc WDR neuronal discharge frequency was significantly greater for noxious than non-noxious stimulation. These results suggest that, in the absence of inflammatory or neuropathic pain, acute intravenous resveratrol administration suppresses trigeminal sensory transmission, including nociception, and so resveratrol may be used as a complementary and alternative medicine therapeutic agent for the treatment of trigeminal nociceptive pain, including hyperalgesia.
Assuntos
Analgésicos/administração & dosagem , Neurônios/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Estilbenos/administração & dosagem , Tato/efeitos dos fármacos , Núcleo Inferior Caudal do Nervo Trigêmeo/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Administração Intravenosa , Animais , Relação Dose-Resposta a Droga , Face/fisiologia , Masculino , Microeletrodos , Neurônios/fisiologia , Nociceptividade/fisiologia , Estimulação Física , Ratos Wistar , Resveratrol , Tato/fisiologia , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologiaRESUMO
Migraine secondary to meningeal input is referred to extracranial regions innervated by somatic afferents that project to homologous regions in the trigeminal nucleus caudalis (TNC). Reported efficacy of extracranial botulinum toxin (BoNT) in treating migraine is surprising since a local extracranial effect of BoNT cannot account for its effect upon meningeal input. We hypothesize that intradermal BoNT acts through central transport in somatic afferents. Anesthetized C57Bl/6 mice (male) received unilateral supraorbital (SO) injections of BoNT-B (1.5 U/40 µl) or saline. 3 days later, mice received ipsilateral (ipsi)-SO capsaicin (20 µl of 0.5mM solution) or meningeal capsaicin (4 µl of 0.35 µM). Pre-treatment with ipsi-SO BoNT-B i) decreased nocicsponsive ipsilateral wiping behavior following ipsi-SO capsaicin; ii) produced cleavage of VAMP in the V1 region of ipsi-TG and in TG neurons showing WGA after SO injection; iii) reduced expression of c-fos in ipsi-TNC following ipsi-SO capsaicin; iv) reduced c-fos activation and NK-1 internalization in ipsi-TNC secondary to ipsi-meningeal capsaicin; and vi) SO WGA did not label dural afferents. We conclude that BoNT-B is taken up by peripheral afferents and transported to central terminals where it inhibits transmitter release resulting in decreased activation of second order neurons. Further, this study supports the hypothesis that SO BoNT exerts a trans-synaptic action on either the second order neuron (which receives convergent input from the meningeal afferent) or the terminal/TG of the converging meningeal afferent.
Assuntos
Toxinas Botulínicas Tipo A/farmacologia , Moduladores de Transporte de Membrana/farmacologia , Transtornos de Enxaqueca/tratamento farmacológico , Neurônios Aferentes/efeitos dos fármacos , Núcleo Inferior Caudal do Nervo Trigêmeo/efeitos dos fármacos , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/patologia , Vias Aferentes/fisiopatologia , Animais , Capsaicina , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Face , Masculino , Meninges/irrigação sanguínea , Meninges/efeitos dos fármacos , Meninges/patologia , Camundongos Endogâmicos C57BL , Transtornos de Enxaqueca/patologia , Transtornos de Enxaqueca/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios Aferentes/patologia , Neurônios Aferentes/fisiologia , Dor Nociceptiva/tratamento farmacológico , Dor Nociceptiva/patologia , Dor Nociceptiva/fisiopatologia , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores da Neurocinina-1/metabolismo , Proteínas SNARE/metabolismo , Pele/efeitos dos fármacos , Pele/inervação , Núcleo Inferior Caudal do Nervo Trigêmeo/patologia , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologiaRESUMO
Cortical spreading depression (SD) is a self-propagating wave of depolarization that is thought to be an underling mechanism of migraine aura. Growing evidence demonstrates that cortical SD triggers neurogenic meningeal inflammation and contributes to migraine headaches via subsequent activation of trigeminal afferents. Although direct and indirect evidence shows that cortical SD activates the trigeminal ganglion (peripheral pathway) and the trigeminal nucleus caudalis (TNC, the first central site of the trigeminal nociceptive pathway), it is not yet known whether cortical SD activates the high-order trigeminal nociceptive pathway in the brain. To address this, we induced unilateral cortical SD in rats, and then examined brain activity using voxel-based statistical parametric mapping analysis of FDG-PET imaging. The results show that approximately 40h after the induction of unilateral cortical SD, regional brain activity significantly increased in several regions, including ipsilateral TNC, contralateral ventral posteromedial (VPM) and posterior thalamic nuclei (Po), the trigeminal barrel-field region of the primary somatosensory cortex (S1BF), and secondary somatosensory cortex (S2). These results suggest that cortical SD is a noxious stimulus that can activate the high-order trigeminal nociceptive pathway even after cortical SD has subsided, probably due to prolonged meningeal inflammation.
Assuntos
Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Transtornos de Enxaqueca/fisiopatologia , Vias Neurais/fisiopatologia , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologia , Nervo Trigêmeo/fisiopatologia , Animais , Modelos Animais de Doenças , Glucose-6-Fosfato/análogos & derivados , Processamento de Imagem Assistida por Computador , Fluxometria por Laser-Doppler , Masculino , Vias Neurais/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Ratos , Ratos Sprague-Dawley , Núcleo Inferior Caudal do Nervo Trigêmeo/diagnóstico por imagem , Nervo Trigêmeo/diagnóstico por imagemRESUMO
BACKGROUND: Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase are transiently phosphorylated (activated) in the spinal cord and trigeminal nucleus by acute noxious stimuli. Acute stimulation of dental pulp induces short-lived ERK activation in trigeminal subnucleus caudalis (Vc), and p38 inhibition attenuates short-term sensitization in Vc induced by acute pulpal stimulation. We have developed a model to study central changes following chronic inflammation of dental pulp that induces long-term sensitization. Here, we examine the effects of chronic inflammation and acute stimulation on the expression of phosphorylated ERK (pERK), phosphorylated p38 (pp38) and Fos in Vc. RESULTS: Chronic inflammation alone induced bilateral expression of pERK and pp38 in Vc, but did not induce Fos expression. Stimulation of both non-inflamed and inflamed pulps significantly increased pERK and pp38 bilaterally; expression was greatest in inflamed, stimulated animals, and was similar following 10-min and 60-min stimulation. Stimulation for 60 min, but not 10 min, induced Fos in ipsilateral Vc; Fos expression was significantly greater in inflamed, stimulated animals. pERK was present in both neurons and astrocytes; pp38 was present in neurons and other non-neuronal, non-astrocytic cell types. CONCLUSIONS: This study provides the first demonstration that chronic inflammation of tooth pulp induces persistent bilateral activation of ERK and p38 within Vc, and that this activation is further increased by acute stimulation. This altered activity in intracellular signaling is likely to be linked to the sensitization that is seen in our animal model and in patients with pulpitis. Our data indicate that pERK and pp38 are more accurate markers of central change than Fos expression. In our model, localization of pERK and pp38 within specific cell types differs from that seen following acute stimulation. This may indicate specific roles for different cell types in the induction and maintenance of pulpitic and other types of pain.
Assuntos
Dor Crônica/fisiopatologia , Pulpite/fisiopatologia , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Astrócitos/fisiologia , Contagem de Células , Dor Crônica/etiologia , Polpa Dentária/fisiopatologia , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Furões , Imuno-Histoquímica , Microscopia de Fluorescência , Neurônios/fisiologia , Fosforilação , Fotomicrografia , Estimulação Física , Proteínas Proto-Oncogênicas c-fos/metabolismo , Pulpite/complicaçõesRESUMO
OBJECTIVE: To examine the hypothesis that glial activation would regulate the expression of the N-methyl-D-aspartate receptor subunit 1 (NR1) in the trigeminal subnucleus caudalis (Sp5C) after temporomandibular joint (TMJ) inflammation. METHODS: Inflammation of TMJ was produced in rats by injecting 50 µL complete Freund's adjuvant (CFA) into unilateral TMJ space. Sham control rats received incomplete Freund's adjuvant injection. Mechanical nociception in the affected and non-affected TMJ site was tested by using a digital algometer. Fractalkine, fluorocitrate, and/or MK801 were intracisternally administrated to examine the relationship between astroglial activation and NR1 upregulation. RESULTS: CFA TMJ injection resulted in persistent ipsilateral mechanical hyperalgesia 1, 3, and 5 days after CFA injection. The inflammation also induced significant upregulation of CX3C chemokine receptor 1 and glial fibrillary acidic protein (GFAP) beginning on day 1 and of NR1 beginning on day 3 within the ipsilateral Sp5C. Intracisternal administration of fluorocitrate for 5 days blocked the development of mechanical hyperalgesia as well as the upregulation of GFAP and NR1 in the Sp5C. Conversely, intracisternal injection of fractalkine for 5 days exacerbated the expression of NR1 in Sp5C and mechanical hyperalgesia induced by TMJ inflammation. Moreover, once daily intracisternal fractalkine administration for 5 days in naïve rats induced the upregulation of NR1 and mechanical hyperalgesia. CONCLUSIONS: These results suggest that astroglial activation contributes to the mechanism of TMJ pain through the regulation of NR1 expression in Sp5C.
Assuntos
Astrócitos/metabolismo , Hiperalgesia/metabolismo , Inflamação/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transtornos da Articulação Temporomandibular/metabolismo , Núcleo Inferior Caudal do Nervo Trigêmeo/metabolismo , Adjuvantes Imunológicos , Animais , Receptor 1 de Quimiocina CX3C , Modelos Animais de Doenças , Adjuvante de Freund , Proteína Glial Fibrilar Ácida/metabolismo , Hiperalgesia/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Masculino , Medição da Dor , Estimulação Física , Ratos , Ratos Sprague-Dawley , Receptores de Quimiocinas/metabolismo , Transtornos da Articulação Temporomandibular/induzido quimicamente , Transtornos da Articulação Temporomandibular/fisiopatologia , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologia , Regulação para CimaRESUMO
The purpose of this study was to assess the temporal relationship between pancreas transplant and the development of electrophysiological changes in the sciatic and caudal nerves of alloxan-induced diabetic rats. Nerve conduction studies were performed in diabetic rats subjected to pancreas transplantation at 4, 12, and 24 weeks after diabetes onset, using non-diabetic and untreated diabetic rats as controls. Nerve conduction data were significantly altered in untreated diabetic control rats up to 48 weeks of follow-up in all time points. Rats subjected to pancreas transplantation up to 4 and 12 weeks after diabetes onset had significantly increased motor nerve conduction velocity with improvement of wave amplitude, distal latency, and temporal dispersion of compound muscle action potential in all follow-up periods (P<0.05); these parameters remained abnormal when pancreas transplantation were performed late at 24 weeks. Our results suggest that early pancreas transplant (at 4-12 weeks) may be effective in controlling diabetic neuropathy in this in vivo model.
Assuntos
Diabetes Mellitus Experimental/cirurgia , Neuropatias Diabéticas/prevenção & controle , Neurônios Motores/metabolismo , Condução Nervosa , Transplante de Pâncreas , Nervo Isquiático/fisiopatologia , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologia , Aloxano , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Progressão da Doença , Hemoglobinas Glicadas/análise , Hiperglicemia/prevenção & controle , Masculino , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Nervo Isquiático/metabolismo , Fatores de Tempo , Transplante Isogênico , Núcleo Inferior Caudal do Nervo Trigêmeo/metabolismoRESUMO
Our electrophysiological studies have shown that both purinergic and glutamatergic receptors are involved in central sensitization of nociceptive neurons in the medullary dorsal horn (MDH). Here we assessed the effects of intrathecal administration of apyrase (a nucleotide degrading enzyme of endogenous adenosine 5-triphosphate [ATP]), a combination of apyrase and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, an adenosine A1 receptor antagonist), or 2,3-O-2,4,6-trinitrophenyl-adenosine triphosphate (TNP-ATP, a P2X1, P2X3, P2X2/3 receptor antagonist) on the release of glutamate in the rat MDH evoked by application of mustard oil (MO) to the molar tooth pulp. In vivo microdialysis was used to dialyse the MDH every 5 min, and included 3 basal samples, 6 samples after drug treatment and 12 samples following application of MO. Tooth pulp application of MO induced a significant increase in glutamate release in the MDH. Superfusion of apyrase or TNP-ATP alone significantly reduced the MO-induced glutamate release in the MDH, as compared to vehicle. Furthermore, the suppressive effects of apyrase on glutamate release were reduced by combining it with DPCPX. This study demonstrates that application of an inflammatory irritant to the tooth pulp induces glutamate release in the rat MDH in vivo that may be reduced by processes involving endogenous ATP and adenosine.
Assuntos
Trifosfato de Adenosina/fisiologia , Sensibilização do Sistema Nervoso Central/fisiologia , Ácido Glutâmico/metabolismo , Irritantes/toxicidade , Mostardeira/toxicidade , Óleos de Plantas/toxicidade , Células do Corno Posterior/metabolismo , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologia , Adenosina/metabolismo , Trifosfato de Adenosina/administração & dosagem , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Animais , Apirase/administração & dosagem , Apirase/farmacologia , Polpa Dentária/efeitos dos fármacos , Polpa Dentária/inervação , Masculino , Microdiálise , Dente Molar , Antagonistas do Receptor Purinérgico P2X/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X/fisiologia , Xantinas/administração & dosagem , Xantinas/farmacologiaRESUMO
To evaluate the involvement of trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) GluR2 and GluR3 subunits in an acute inflammatory orofacial pain, we analyzed nocifensive behavior, phosphorylated extracellular signal-regulated kinase (pERK) and Fos expression in Vi/Vc, Vc and C1/C2 in GluR2 delta7 knock-in (KI), GluR3 delta7 KI mice and wild-type mice. We also studied Vc neuronal activity to address the hypothesis that trafficking of GluR2 and GluR3 subunits plays an important role in Vi/Vc, Vc and C1/C2 neuronal activity associated with orofacial inflammation in these mice. Late nocifensive behavior was significantly depressed in GluR2 delta7 KI and GluR3 delta7 KI mice. In addition, the number of pERK-immunoreactive (IR) cells was significantly decreased bilaterally in the Vi/Vc, Vc and C1/C2 in GluR2 delta7 KI and GluR3 delta7 KI mice compared to wild-type mice at 40 min after formalin injection, and was also significantly smaller in GluR3 delta7 KI compared to GluR2 delta7 KI mice. The number of Fos protein-IR cells in the ipsilateral Vi/Vc, Vc and C1/C2 was also significantly smaller in GluR2 delta7 KI and GluR3 delta7 KI mice compared to wild-type mice 40 min after formalin injection. Nociceptive neurons functionally identified as wide dynamic range neurons in the Vc, where pERK- and Fos protein-IR cell expression was prominent, showed significantly lower spontaneous activity in GluR2 delta7 KI and GluR3 delta7 KI mice than wild-type mice following formalin injection. These findings suggest that GluR2 and GluR3 trafficking is involved in the enhancement of Vi/Vc, Vc and C1/C2 nociceptive neuronal excitabilities at 16-60 min following formalin injection, resulting in orofacial inflammatory pain.
Assuntos
Dor Aguda/metabolismo , Dor Facial/metabolismo , Nociceptores/metabolismo , Receptores de AMPA/metabolismo , Núcleo Inferior Caudal do Nervo Trigêmeo/metabolismo , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Dor Aguda/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Dor Facial/fisiopatologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Camundongos , Camundongos Transgênicos , Nociceptores/efeitos dos fármacos , Medição da Dor , Fosforilação/efeitos dos fármacos , Núcleo Inferior Caudal do Nervo Trigêmeo/efeitos dos fármacos , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologiaAssuntos
Neuralgia/diagnóstico , Odontalgia/diagnóstico , Dor Crônica/fisiopatologia , Dor Crônica/terapia , Diagnóstico Diferencial , Feminino , Humanos , Vias Neurais/fisiopatologia , Neuralgia/fisiopatologia , Neuralgia/terapia , Manejo da Dor , Terminologia como Assunto , Ápice Dentário/inervação , Odontalgia/fisiopatologia , Odontalgia/terapia , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologia , Gânglio Trigeminal/fisiopatologiaRESUMO
Previous studies have established the role of the medullary dorsal horn or the subnucleus caudalis of the spinal trigeminal complex, a homolog of the dorsal horn of the spinal cord, in trigeminal pain processing. In addition to the medullary dorsal horn, recent studies have pointed out increased excitability and sensitization of trigeminal interpolaris and caudalis transition zone (Vi/Vc) following deep orofacial injury, involving neuron-glia-cytokine interactions. The Vi/Vc transition zone accesses rostral brain regions that are important for descending pain modulation, and somatovisceral and somatoautonomic processing and plays a unique role in coordinating trigeminal nocifensive responses.
Assuntos
Dor Facial/patologia , Músculo Masseter/fisiopatologia , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologia , Vias Aferentes/fisiopatologia , Animais , Citocinas/metabolismo , Humanos , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Nociceptores/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Células Receptoras Sensoriais/fisiologia , Núcleo Inferior Caudal do Nervo Trigêmeo/patologiaRESUMO
The mechanisms underlying neuropathic facial pain syndromes are incompletely understood. We used a unilateral chronic constriction injury of the rat infraorbital nerve (CCI-IoN) as a facial neuropathic model. Pain-related behavior of the CCI-IoN animals was tested at 8, 15 and 26 days after surgery (dps). The response threshold to mechanical stimulation with von Frey hairs on the injured side was reduced at 15 and 26 dps, indicating the presence of allodynia. We performed unitary recordings in the caudalis division of the spinal trigeminal nucleus (Sp5C) at 8 or 26 dps, and examined spontaneous activity and responses to mechanical and thermal stimulation of the vibrissal pad. Neurons were identified as wide dynamic range (WDR) or low-threshold mechanoreceptive (LTM) according to their response to tactile and/or noxious stimulation. Following CCI-IoN, WDR neurons, but not LTM neurons, increased their spontaneous activity at 8 and 26 dps, and both types of Sp5C neurons increased their responses to tactile stimuli. In addition, the on-off tactile response in neurons recorded after CCI-IoN was followed by afterdischarges that were not observed in control cases. Compared with controls, the response inhibition observed during paired-pulse stimulation was reduced after CCI-IoN. Immunohistochemical studies showed an overall decrease in GAD65 immunoreactivity in Sp5C at 26 dps, most marked in laminae I and II, suggesting that following CCI-IoN the inhibitory circuits in the sensory trigeminal nuclei are depressed. Consequently, our results strongly suggest that disinhibition of Sp5C neurons plays a relevant role in the appearance of allodynia after CCI-IoN.
Assuntos
Inibição Neural/fisiologia , Neuralgia/fisiopatologia , Neurônios/fisiologia , Núcleo Inferior Caudal do Nervo Trigêmeo/fisiopatologia , Animais , Comportamento Animal/fisiologia , Contagem de Células , Doença Crônica , Eletrofisiologia , Glutamato Descarboxilase/metabolismo , Imuno-Histoquímica , Masculino , Neuralgia/metabolismo , Medição da Dor , Limiar da Dor/fisiologia , Estimulação Física , Ratos , Ratos Sprague-Dawley , Núcleo Inferior Caudal do Nervo Trigêmeo/metabolismoRESUMO
This review was developed as part of a debate, and takes the "pro" stance that abnormalities of structures in the neck can be a significant source of headache. The argument for this is developed from a review of the medical literature, and is made in 5 steps. It is clear that the cervical region contains many pain-sensitive structures, and that these are prone to injury. The anatomical and physiological mechanisms are in place to allow referral of pain to the head including frontal head regions and even the orbit in patients with pain originating from many of these neck structures. Clinical studies have shown that pain from cervical spine structures can in fact be referred to the head. Finally, clinical treatment trials involving patients with proven painful disorders of upper cervical zygapophysial joints have shown significant headache relief with treatment directed at cervical pain generators. In conclusion, painful disorders of the neck can give rise to headache, and the challenge is to identify these patients and treat them successfully.