RESUMEN

Patients with persistent and severe dry eye disease (DED) have corneal hypersensitivity, resulting in ocular pain, and diquafosol sodium, a potent P2Y2 receptor agonist, is commonly used to improve the resultant tear film stability. This study determined the effects of diquafosol instillation on the suppression of trigeminal subnucleus caudalis (Vc) neuronal activity and ocular pain by enhancing tear film stability in the model for chronic DED. The effects of diquafosol on the ocular surface were assessed by the topical application for 28 days, starting from the 14th day since unilateral exorbital gland removal (chronic DED). Loss of tear volume secretion in chronic DED rats was significantly reversed by diquafosol instillation after 28 days, compared with saline treatment. The number of eyeblinks and pERK-IR neurons in the superficial laminae of Vc following hypertonic saline administration to the ocular surface was lower in diquafosol-treated chronic DED rats than in saline-treated rats. The neuronal activity evoked by hypertonic saline and mechanical stimulation along with the spontaneous neuronal activity in the superficial laminae of the Vc were suppressed in diquafosol-treated chronic DED rats. These findings suggest that ocular surface instillation of diquafosol for 28 days attenuates the neuronal hyperactivity in the Vc and the ocular pain that often occurs in chronic DED.

Asunto(s)

Síndromes de Ojo Seco , Sodio , Ratas , Animales , Nucleótidos de Uracilo/farmacología , Síndromes de Ojo Seco/tratamiento farmacológico , Lágrimas , Neuronas , Dolor , Soluciones Oftálmicas/farmacología

RESUMEN

The nerve growth factor (NGF) and calcitonin gene-related peptide (CGRP) play a crucial role in the regulation of orofacial pain. It has been demonstrated that CGRP increases orofacial pain induced by NGF. V-type proton ATPase subunit an isoform 1 (Atp6v0a1) is involved in the exocytosis pathway, especially in vesicular transport in neurons. The objective was to examine the role of Atp6v0a1 in NGF-induced upregulation of CGRP in orofacial pain induced by experimental tooth movement. Orofacial pain was elicited by ligating closed-coil springs between incisors and molars in Sprague-Dawley rats. Gene and protein expression levels were determined through real-time polymerase chain reaction, immunostaining, and fluorescence in situ hybridization. Lentivirus vectors carrying Atp6v0a1 shRNA were used to knockdown the expression of Atp6v0a1 in TG and SH-SY5Y neurons. The release of vesicles in SH-SY5Y neurons was observed by using fluorescence dye FM1-43, and the release of CGRP was detected by Enzyme-Linked Immunosorbent Assy. Orofacial pain was evaluated through the rat grimace scale. Our results revealed that intraganglionic administration of NGF and Atp6v0a1 shRNA upregulated and downregulated CGRP in trigeminal ganglia (TG) and trigeminal subnucleus caudalis (Vc), respectively, and the orofacial pain was also exacerbated and alleviated, respectively, following administration of NGF and Atp6v0a1 shRNA. Besides, intraganglionic administration of NGF simultaneously caused the downregulation of Atp6v0a1 in TG. Moreover, the release of vesicles and CGRP in SH-SY5Y neurons was interfered by NGF and Atp6v0a1 shRNA. In conclusion, in the orofacial pain induced by experimental tooth movement, NGF induced the upregulation of CGRP in TG and Vc, and this process is dependent on Atp6v0a1 and vesicle release, suggesting that they are involved in the transmission of nociceptive information in orofacial pain.

Asunto(s)

Péptido Relacionado con Gen de Calcitonina , Dolor Facial , Factor de Crecimiento Nervioso , Técnicas de Movimiento Dental , ATPasas de Translocación de Protón Vacuolares , Adenosina Trifosfatasas/metabolismo , Animales , Péptido Relacionado con Gen de Calcitonina/genética , Péptido Relacionado con Gen de Calcitonina/metabolismo , Exocitosis/genética , Exocitosis/fisiología , Dolor Facial/etiología , Dolor Facial/genética , Dolor Facial/metabolismo , Inmunoadsorbentes , Hibridación Fluorescente in Situ , Factor de Crecimiento Nervioso/genética , Factor de Crecimiento Nervioso/metabolismo , Neuroblastoma , Neuronas/metabolismo , Nocicepción/fisiología , Protones , ARN Interferente Pequeño , Ratas , Ratas Sprague-Dawley , Técnicas de Movimiento Dental/métodos , Regulación hacia Arriba , ATPasas de Translocación de Protón Vacuolares/genética , ATPasas de Translocación de Protón Vacuolares/metabolismo

RESUMEN

The present study examined contribution of the transient receptor potential vanilloid 1 channel (TRPV1) to the chronic orofacial pain. Bilateral partial nerve ligation (PNL) of the mental nerve, a branch of trigeminal nerve, was performed to induce neuropathic pain. The withdrawal threshold in response to mechanical stimulation of the lower lip skin was substantially reduced after the surgery in the PNL rats while it remained unchanged in the sham rats. This reduction in the PNL rats was alleviated by pregabalin injected intraperitoneally (10 mg/kg) and intracisternally (10, 30, 100 µg). Furthermore, an intracisternal injection of AMG9810, an antagonist of TRPV1, (1.5, 5.0 µg) attenuated the reduction of withdrawal threshold. Spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) were recorded from the spinal trigeminal subnucleus caudalis (Vc) neurons in the brainstem slice, which receive the orofacial nociceptive signals. In the PNL rats, superfusion of capsaicin (0.03, 0.1 µM) enhanced their frequency without effect on the amplitude and the highest concentration (0.3 µM) increased both the frequency and amplitude. In the sham rats, only 0.3 µM capsaicin increased their frequency. Thus, capsaicin-induced facilitation of sEPSCs and mEPSCs in the PNL rats was significantly stronger than that in the sham rats. AMG9810 (0.1 µM) attenuated the capsaicin's effect. Capsaicin was ineffective on the trigeminal tract-evoked EPSCs in the PNL and sham rats. These results suggest that the chronic orofacial pain in the PNL model results from facilitation of the spontaneous excitatory synaptic transmission in the Vc region through TRPV1 at least partly.

Asunto(s)

Dolor Crónico/patología , Dolor Facial/patología , Neuralgia/patología , Canales Catiónicos TRPV/metabolismo , Núcleo Caudal del Trigémino/metabolismo , Animales , Capsaicina/administración & dosificación , Capsaicina/toxicidad , Dolor Crónico/inducido químicamente , Dolor Crónico/tratamiento farmacológico , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Dolor Facial/inducido químicamente , Dolor Facial/tratamiento farmacológico , Humanos , Masculino , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Transmisión Sináptica/efectos de los fármacos , Canales Catiónicos TRPV/antagonistas & inhibidores , Núcleo Caudal del Trigémino/citología , Núcleo Caudal del Trigémino/efectos de los fármacos

RESUMEN

Chronic pain in temporomandibular disorder (TMD) is a common health problem. Cumulating evidence indicates that the etiology of TMD pain is complex with multifactorial experience that could hamper the developments of treatments. Preclinical research is a resource to understand the mechanism for TMD pain, whereas limitations are present as a disease-specific model. It is difficult to incorporate multiple risk factors associated with the etiology that could increase pain responses into a single animal. This article introduces several rodent models which are often employed in the preclinical studies and discusses their validities for TMD pain after the elucidations of the neural mechanisms based on the clinical reports. First, rodent models were classified into two groups with or without inflammation in the deep craniofacial tissues. Next, the characteristics of each model and the procedures to identify deep craniofacial pain were discussed. Emphasis was directed on the findings of the effects of chronic psychological stress, a major risk factor for chronic pain, on the deep craniofacial nociception. Preclinical models have provided clinically relevant information, which could contribute to better understand the basis for TMD pain, while efforts are still required to bridge the gap between animal and human studies.

RESUMEN

Neuropathic pain is characterized by sensory abnormalities, such as mechanical allodynia and heat hyperalgesia, associated with alteration in the peripheral and central nervous systems. After trigeminal nerve injury, phenotypic changes that involve the expression of calcitonin gene-related peptide occur in large- and medium-sized myelinated neurons; primary afferent neurons exhibit hyperexcitability because of neuron-glia interactions in the trigeminal ganglion. Increased nociceptive inputs from C- and Aδ-fiber and innocuous inputs from Aß-fiber into the trigeminal spinal subnucleus caudalis (Vc) contribute to the phenotypic changes; further, they potentiate noxious information transmission in the ascending nociceptive pathways to the thalamus and parabrachial nucleus (PBN). It is noteworthy that C-fiber mediated nociceptive inputs can activate both the Vc-ventral posteromedial thalamic nucleus and Vc-PBN pathways, while mechanoreceptive fiber inputs specifically activate the Vc-PBN pathway. The Vc-PBN pathways project to the central nucleus of the amygdala (CeA) where affective behaviors are modulated. In addition, the PBN interacts with wakefulness-regulating neurons and hunger-sensitive neurons in the hypothalamus, suggesting that the Vc-PBN pathway can modulate sleep and appetite. Therefore, phenotypic changes in primary neurons and stimulus modality-specific activation of ascending nociceptive pathways to the PBN may exacerbate affective aspects of trigeminal neuropathic pain, including behavioral problems, such as sleep disturbance and anorexia, via the PBN-CeA-hypothalamus circuits.

Asunto(s)

Neuralgia , Núcleos Parabraquiales , Péptido Relacionado con Gen de Calcitonina , Humanos , Neuronas

RESUMEN

The signs and symptoms of persistent temporomandibular joint (TMJ)/muscle disorder (TMJD) pain suggest the existence of a central neural dysfunction or a problem of pain amplification. The etiology of chronic TMJD is not known; however, female sex hormones have been identified as significant risk factors. Converging lines of evidence indicate that the junctional region between the trigeminal subnucleus caudalis (Vc) and the upper cervical spinal cord, termed the Vc/C1-2 region, is the primary site for the synaptic integration of sensory input from TMJ nociceptors. In this paper, the mechanisms behind the estrogen effects on the processing of nociceptive inputs by neurons in the Vc/C1-2 region reported by human and animal studies are reviewed. The Vc/C1-2 region has direct connections to endogenous pain and autonomic control pathways, which are modified by estrogen status and are suggested to be critical for somatomotor and autonomic reflex responses of TMJ-related sensory signals.

Asunto(s)

Estrógenos , Núcleo Caudal del Trigémino , Animales , Femenino , Neuronas , Dolor , Ratas , Ratas Sprague-Dawley , Articulación Temporomandibular

RESUMEN

OBJECTIVE: To observe the effect of occlusal interference on the afferent pathway of the trigeminal nerve and neuronal excitability in the trigeminal subnucleus caudalis (SPVC) of rats by electrical stimulation of the trigeminal ganglion (TG) and extracellular recordings of SPVC activities. METHODS: Twenty male Wistar rats were randomly divided into control group and model group (n=10). In the model group, occlusal interference for 30 consecutive days was induced using light-cured flowable resin on the right maxillary molars. During occlusal interference, the pain sensitivity was scored with von Frey Fibers in the masseter. Simultaneous recordings of electrical activities from the SPVC, electrocardiogram, body temperature and electromyogram of the breath muscles of the anesthetized rats were performed, and the responses evoked by electrical stimulation of the TG were analyzed. RESULTS: Compared with the control rats, the rats in the model group showed significantly increased pain sensitivity scores (P < 0.05) and increased spontaneous discharge frequency of the SPVC (P < 0.05). The amplitude of the SPVC responses induced by electrical stimulation of the TG showed stimulus intensity-dependent changes (P < 0.05), and the amplitude evoked by 4 mA and 8 mA stimulation was similar between the model group and the control group (P>0.05). Train stimulation (0.2 ms, 1 mA, 30 s, 100 Hz) of the TG significantly increased the discharge frequency of the SPVC only in the rats in the model group (P < 0.05). CONCLUSIONS: The functional activities of the pain afferent pathway of the trigeminal nerve can be electrophysiologically monitored by electrical stimulation of the TG and extracellular recordings of SPVC activities in rats. Occlusal interference can increase the excitability of the neurons in the SPVC and enhance their sensitivities to TG afferent activation, suggesting the neural plasticity of the pain afferent pathway.

Asunto(s)

Vías Aferentes , Dimensión del Dolor , Umbral del Dolor , Dolor/fisiopatología , Nervio Trigémino/fisiología , Animales , Masculino , Distribución Aleatoria , Ratas , Ratas Wistar , Núcleos del Trigémino

RESUMEN

Prostaglandin E2 (PGE2) synthesized in the central nervous system influences various physiological functions including nociception. Recently, we have demonstrated that PGE2 facilitates spontaneous synaptic transmission through presynaptic EP1 receptors in the spinal trigeminal subnucleus caudalis (Vc) neurons that receive nociceptive signals from the orofacial area. Increasing evidence suggests that the action of PGE2 is related to activation of transient receptor potential vanilloid 1 (TRPV1) channels. The present study investigated whether TRPV1 channels contribute to the facilitatory effect of PGE2 on synaptic transmission in the Vc neurons. Spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) were recorded from Vc neurons in the rat brainstem slice by whole-cell patch-clamp mode. Superfusion of capsaicin (0.3, 1.0 µM) concentration-dependently increased the frequency of both sEPSCs and sIPSCs without any significant effect on their amplitude. The effect of capsaicin was completely abolished by a TRPV1 channel blocker AMG9810 (0.1 µM). PGE2 (5.0 µM) increased the frequency of sEPSCs and sIPSCs. This facilitatory effect of PGE2 was attenuated by AMG9810 and in neurons desensitized by repeated application of capsaicin. While a low concentration of either PGE2 (1.0 µM) or capsaicin (0.1 µM) had an insignificant effect on the sEPSCs and sIPSCs, co-application of these drugs increased their frequency. The present study demonstrated involvement of the presynaptic TRPV1 channels in PGE2-induced facilitation of spontaneous synaptic transmissions and suggests interaction of PGE2 with TRPV1 channels in modification of nociceptive signals from the orofacial area to the Vc neurons.

Asunto(s)

Dinoprostona/farmacología , Transmisión Sináptica/efectos de los fármacos , Canales Catiónicos TRPV/metabolismo , Núcleo Espinal del Trigémino/efectos de los fármacos , Animales , Dinoprostona/metabolismo , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Masculino , Neuronas/metabolismo , Nocicepción/fisiología , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Núcleo Espinal del Trigémino/metabolismo

RESUMEN

OBJECTIVE@#To observe the effect of occlusal interference on the afferent pathway of the trigeminal nerve and neuronal excitability in the trigeminal subnucleus caudalis (SPVC) of rats by electrical stimulation of the trigeminal ganglion (TG) and extracellular recordings of SPVC activities.@*METHODS@#Twenty male Wistar rats were randomly divided into control group and model group (=10). In the model group, occlusal interference for 30 consecutive days was induced using light-cured flowable resin on the right maxillary molars. During occlusal interference, the pain sensitivity was scored with von Frey Fibers in the masseter. Simultaneous recordings of electrical activities from the SPVC, electrocardiogram, body temperature and electromyogram of the breath muscles of the anesthetized rats were performed, and the responses evoked by electrical stimulation of the TG were analyzed.@*RESULTS@#Compared with the control rats, the rats in the model group showed significantly increased pain sensitivity scores ( 0.05). Train stimulation (0.2 ms, 1 mA, 30 s, 100 Hz) of the TG significantly increased the discharge frequency of the SPVC only in the rats in the model group ( < 0.05).@*CONCLUSIONS@#The functional activities of the pain afferent pathway of the trigeminal nerve can be electrophysiologically monitored by electrical stimulation of the TG and extracellular recordings of SPVC activities in rats. Occlusal interference can increase the excitability of the neurons in the SPVC and enhance their sensitivities to TG afferent activation, suggesting the neural plasticity of the pain afferent pathway.

RESUMEN

This study aimed to determine whether psychophysical stress conditionings had facilitatory effects on masseter muscle nociception in the central nervous system via serotonergic mechanisms in rats. Two experiments were conducted to assess: (1) whether repeated forced swim stress for 3 days increased the number of Fos-positive neurons evoked by masseter muscle injury due to formalin injection; and (2) whether serotonin-reuptake inhibitor, fluoxetine, administered daily after each stress conditioning, had modulatory roles on Fos expression. The number of Fos-positive cells was quantified in several areas within the trigeminal subnucleus caudalis (Vc) and upper cervical spinal cord regions (Vc areas), including the ventrolateral area of the trigeminal subnucleus interpolaris/Vc transition, and the middle or caudal portion of the Vc regions, since nociceptive neural activity in the Vc region could play critical roles in deep craniofacial nociception. We found that forced swim stress conditionings increased depression-like behaviors, which was prevented by fluoxetine. Repeated forced swim stress significantly increased Fos expression in all Vc areas compared with those of non-stressed rats, while systemic administration of fluoxetine significantly decreased Fos expression in all areas, but mainly in the caudal Vc region, in stressed rats. Fluoxetine had no effect on Fos expression in non-stressed rats. These results indicate that repeated forced swim stress conditionings increase Fos expression in the Vc areas, and the contribution of serotonergic mechanisms to masseter muscle nociception could be greater in stressed rats than in sham rats. These results support the hypothesis that changes in brain function, including serotonergic mechanisms, in the Vc areas play critical roles in enhanced masseter muscle nociceptive responses under psychophysical stress conditions.

Asunto(s)

Antidepresivos/farmacología , Fluoxetina/farmacología , Mialgia/metabolismo , Médula Espinal/patología , Estrés Psicológico/patología , Núcleos del Trigémino/patología , Animales , Antidepresivos/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Fluoxetina/uso terapéutico , Formaldehído/toxicidad , Lateralidad Funcional , Masculino , Mialgia/inducido químicamente , Nocicepción/efectos de los fármacos , Proteínas Oncogénicas v-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Médula Espinal/metabolismo , Estrés Psicológico/tratamiento farmacológico , Natación

RESUMEN

We determined the role of persistent monoarthritis of temporomandibular joint region (TMJ) on bilateral masseter muscle (MM) nociception in male rats using orofacial nocifensive behaviors, phosphorylated extracellular signal-regulated kinase and Fos induction at the trigeminal subnucleus caudalis/upper cervical spinal cord (Vc/C2) region in response to formalin injection to the MM region. TMJ inflammation was induced by local injection of CFA into the left TMJ region. Orofacial nocifensive behaviors evoked by formalin injection ipsilateral or contralateral to the TMJ inflammation appeared to be increased at 1-14 days or at 1, 10 and 14 days after induction of TMJ inflammation, respectively, while increases in behavioral duration were seen mainly in the late phase rather than the early phase. The number of pERK positive cells was investigated in superficial laminae at the Vc/C2 region at 3, 10, 20, 60 and 80 min after MM stimulation with formalin at 14 days after TMJ inflammation. TMJ-inflamed rats displayed greater responses of pERK expression by the ipsilateral MM stimulation at 3-60 min, while contralateral MM stimulation increased pERK expression at 3, 10 and 20 min compared to non-CFA rats. Fos expression by MM stimulation was increased at 14 days after induction of TMJ inflammation regardless of the affected side. These findings showed that persistent TMJ inflammation for 10 and 14 days is sufficient to enhance MM nociception indicated by behaviors and neural responses in superficial laminae at the Vc/C2 region.

Asunto(s)

Lateralidad Funcional/fisiología , Inflamación/complicaciones , Enfermedades Musculares/etiología , Vías Nerviosas/metabolismo , Síndrome de la Disfunción de Articulación Temporomandibular/complicaciones , eIF-2 Quinasa/metabolismo , Animales , Modelos Animales de Enfermedad , Formaldehído/efectos adversos , Adyuvante de Freund/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Músculo Masetero/patología , Enfermedades Musculares/patología , Proteínas Oncogénicas v-fos/metabolismo , Dimensión del Dolor , Ratas , Ratas Sprague-Dawley , Síndrome de la Disfunción de Articulación Temporomandibular/inducido químicamente , Factores de Tiempo

RESUMEN

Extensive studies have focused on the development and regionalization of neurons in the central nervous system (CNS). Many genes, which play crucial roles in the development of CNS neurons, have been identified. By using the technique "direct reprogramming", neurons can be produced from multiple cell sources such as fibroblasts. However, understanding the region-specific regulation of neurons in the CNS is still one of the biggest challenges in the research field of neuroscience. Neurons located in the trigeminal subnucleus caudalis (Vc) and in the spinal dorsal horn (SDH) play crucial roles in pain and sensorimotor functions in the orofacial and other somatic body regions, respectively. Anatomically, Vc represents the most caudal component of the trigeminal system, and is contiguous with SDH. This review is focused on recent data dealing with the regional specificity involved in the development of neurons in Vc and SDH.

RESUMEN

Acid-sensing ion channels (ASICs) are widely expressed in both the peripheral and central nervous system, and contribute to the modulation of central nociceptive transmission under both physiological and pathophysiological conditions. In this study, we characterized the proton-induced membrane currents in acutely isolated rat substantia gelatinosa (SG) neurons of the trigeminal subnucleus caudalis using the whole cell patch-clamp technique. Exposure to acidic conditions (pH<6.5) induced the inward currents in a pH-dependent manner. Amiloride, a general ASIC antagonist, significantly blocked the proton-induced currents in a non-competitive manner. The pH 6.0-induced membrane current (IpH6.0) was greatly attenuated in the Na(+)-free external solution, and the reversal potential of the proton-induced currents was similar to the theoretical Na(+) equilibrium potential. The IpH6.0 was reciprocally potentiated by a lower extracellular Ca(2+) concentration. The modulation of IpH6.0 by divalent cations and other modulators suggests that the proton-induced currents are mediated by multiple types of ASIC subunits, including ASIC1a and ASIC2a. Multi-cell RT-PCR analysis revealed that SG neurons express these subunits. Exposure to a pH 6.0 solution directly depolarized the membrane potential, and generated a burst of action potentials in a current-clamp mode. This acidic pH-induced depolarization was significantly blocked by amiloride. The present results suggest that ASICs expressed on SG neurons play important roles in the regulation of nociceptive transmission from the orofacial tissues.

Asunto(s)

Fenómenos Electrofisiológicos/efectos de los fármacos , Protones , Sustancia Gelatinosa/citología , Sustancia Gelatinosa/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/farmacología , Ácido Araquidónico/farmacología , Cationes Bivalentes/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Ácido Láctico/farmacología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Ratas , Ratas Sprague-Dawley

RESUMEN

Repeated forced swim (FS) conditioning enhances nociceptive responses to temporomandibular joint (TMJ) stimulation in female rats. The basis for FS-induced TMJ hyperalgesia remains unclear. To test the hypothesis that serotonin 3 receptor (5HT3R) mechanisms contribute to enhanced TMJ nociception after FS, ovariectomized female rats were treated with estradiol and subjected to FS for three days. On day 4, rats were anesthetized with isoflurane and TMJ-responsive neurons were recorded from superficial and deep laminae at the trigeminal subnucleus caudalis/upper cervical (Vc/C1-2) region and electromyographic (EMG) activity was recorded from the masseter muscle. Only Vc/C1-2 neurons activated by intra-TMJ injections of ATP were included for further analysis. Although neurons in both superficial and deep laminae were activated by ATP, only neurons in deep laminae displayed enhanced responses after FS. Local application of the 5HT3R antagonist, ondansetron (OND), at the Vc/C1-2 region reduced the ATP-evoked responses of neurons in superficial and deep laminae and reduced the EMG response in both sham and FS rats. OND also decreased the spontaneous firing rate of neurons in deep laminae and reduced the high-threshold convergent cutaneous receptive field area of neurons in superficial and deep laminae in both sham and FS rats. These results revealed that central application of a 5HT3R antagonist, had widespread effects on the properties of TMJ-responsive neurons at the Vc/C1-2 region and on jaw muscle reflexes under sham and FS conditions. It is concluded that 5HT3R does not play a unique role in mediating stress-induced hyperalgesia related to TMJ nociception.

Asunto(s)

Bulbo Raquídeo/fisiopatología , Neuronas/fisiología , Nocicepción/fisiología , Receptores de Serotonina 5-HT3/fisiología , Estrés Psicológico/fisiopatología , Articulación Temporomandibular/fisiología , Adenosina Trifosfato/farmacología , Animales , Electromiografía , Femenino , Músculo Masetero/inervación , Músculo Masetero/fisiología , Bulbo Raquídeo/efectos de los fármacos , Neuronas/efectos de los fármacos , Ondansetrón/farmacología , Ovariectomía , Ratas , Ratas Sprague-Dawley , Antagonistas del Receptor de Serotonina 5-HT3/farmacología , Articulación Temporomandibular/efectos de los fármacos , Articulación Temporomandibular/inervación

RESUMEN

The roles of persistent Na(+) currents (INaP) in intrinsic membrane properties were examined in rat substantia gelatinosa (SG) neurons of the trigeminal subnucleus caudalis using a conventional whole-cell patch clamp technique. In a voltage-clamp mode, riluzole inhibited the slow voltage ramp-induced INaP but had little effect on the peak amplitude of transient Na(+) currents in SG neurons. In a current-clamp mode, most SG neurons exhibited spontaneous action potentials and tonic firing pattern. Riluzole reduced both spontaneous and elicited action potentials in a concentration-dependent manner. The present results suggest that the riluzole-sensitive INaP plays an important role in the excitability of SG neurons and are thus, likely to contribute to the modulation of nociceptive transmission from the orofacial tissues.

Asunto(s)

Potenciales de Acción , Neuronas/fisiología , Sustancia Gelatinosa/fisiología , Canales de Sodio Activados por Voltaje/fisiología , Animales , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Ratas Sprague-Dawley , Riluzol/farmacología

RESUMEN

BACKGROUND: Pain constitutes the major non motor syndrome in Parkinson's disease (PD) and includes neuropathic pain; however current drug therapies used to alleviate it have only limited efficacy. This is probably due to poor understanding of the mechanisms underlying it. AIMS: We investigated a major class of trigeminal neuropathic pain, dynamic mechanical allodynia (DMA), in a rat model of PD and in which a bilateral 6-hydroxy dopamine (6-OHDA) injection was administered to produce a lesion of the nigrostriatal dopaminergic pathway. RESULTS AND DISCUSSION: Lesioned animals presented significant DMA in the orofacial area that occurred from 4 days to 5 weeks post-injury. To investigate a segmental implication in the neuropathic pain induced by dopamine depletion, the expression of the isoform gamma of the protein kinase C (PKCg) and phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2) was explored in the medullary dorsal horn (MDH). There was a high increase in PKCg expression in the III and IIi laminae of the MDH of lesioned-animals compared to shams. pERK1/2 expression was also significantly high in the ipsilateral MDH of lesioned rats in response to non-noxious tactile stimulus of the orofacial region. Since pERK1/2 is expressed only in response to nociceptive stimuli in the dorsal spinal horn, the current study demonstrates that non-noxious stimuli evoke allodynic response. Intraperitoneal and intracisternal administrations of bromocriptine, a dopamine 2 receptor (D2R) agonist, significantly decreased DMA compared to control rats injected with saline. These data demonstrate for the first time that nigrostriatal dopaminergic depletion produces trigeminal neuropathic pain that at least involves a segmental mechanism. In addition, bromocriptine was shown to have a remarkable analgesic effect on this neuropathic pain symptom.

Asunto(s)

Cuerpo Estriado/fisiopatología , Neuronas Dopaminérgicas/efectos de los fármacos , Hiperalgesia/inducido químicamente , Enfermedad de Parkinson Secundaria/fisiopatología , Sustancia Negra/fisiopatología , Neuralgia del Trigémino/inducido químicamente , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiopatología , Oxidopamina , Dimensión del Dolor , Enfermedad de Parkinson Secundaria/metabolismo , Fosforilación , Estimulación Física , Ratas , Ratas Sprague-Dawley , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Neuralgia del Trigémino/metabolismo , Neuralgia del Trigémino/fisiopatología

RESUMEN

The incidence of chronic oral pain such as burning mouth syndrome is greater in peri-menopausal females, and was postulated to be associated with gustatory nerve damage. We investigated whether bilateral transection of the chorda tympani, with or without accompanying ovariectomy, affected oral capsaicin avoidance in rats. Female rats had restricted access to 2 bottles, 1 bottle containing capsaicin (concentration range: 0.33-33 µM/L) and the other vehicle. Percent volume of capsaicin consumption and lick counts were measured. The concentration series was tested before and 0.5, 3, 6, 9, and 12 months after the following surgical procedures: (a) bilateral transection of the chorda tympani (CTx); (b) ovariectomy (OVx); (3) CTx plus OVx; or (4) sham CT surgery. Before surgery there was a concentration-dependent decrease in licks and volume of capsaicin consumed, with a threshold between 0.1 and 0.3 ppm. The majority of drink licks occurred during the first 9 minutes of access. Over the 12-month test period, the CTx group did not exhibit reduced capsaicin consumption, and consumed significantly more capsaicin at 6 and 9 months postsurgery. Rats in the OVx group consistently consumed significantly less capsaicin and exhibited significantly higher counts of capsaicin-evoked Fos-like immunoreactivity in the dorsomedial trigeminal subnucleus caudalis (Vc) compared to all other treatment groups. That CTx, with or without OVx, did not enhance capsaicin avoidance indicates that damage to the gustatory system does not disinhibit trigeminal nociceptive transmission.

Asunto(s)

Capsaicina/toxicidad , Nervio de la Cuerda del Tímpano/fisiología , Dolor Facial/inducido químicamente , Fármacos del Sistema Sensorial/toxicidad , Análisis de Varianza , Animales , Peso Corporal/efectos de los fármacos , Conducta de Elección/fisiología , Nervio de la Cuerda del Tímpano/cirugía , Relación Dosis-Respuesta a Droga , Conducta de Ingestión de Líquido/efectos de los fármacos , Conducta de Ingestión de Líquido/fisiología , Dolor Facial/fisiopatología , Femenino , Masculino , Proteínas Oncogénicas v-fos/metabolismo , Ovariectomía , Ratas , Factores de Tiempo

RESUMEN

While considerable effort has been made to investigate the neural mechanisms of pain, much less effort has been devoted to itch, at least until recently. However, itch is now gaining increasing recognition as a widespread and costly medical and socioeconomic issue. This is accompanied by increasing interest in the underlying neural mechanisms of itch, which has become a vibrant and rapidly-advancing field of research. The goal of the present forefront review is to describe the recent progress that has been made in our understanding of itch mechanisms.

Asunto(s)

Prurito/fisiopatología , Analgésicos Opioides/farmacología , Animales , Modelos Animales de Enfermedad , Fenómenos Electrofisiológicos/efectos de los fármacos , Fenómenos Electrofisiológicos/fisiología , Humanos , Interneuronas/fisiología , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/fisiología , Neurotransmisores/fisiología , Prurito/inducido químicamente , Transducción de Señal/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiología , Nervio Trigémino/fisiopatología

RESUMEN

UNLABELLED: We previously developed a rat dental occlusal interference model of facial pain that was produced by bonding a crown onto the right maxillary first molar and was reflected in sustained facial hypersensitivity that was suggestive of the involvement of central sensitization mechanisms. The aim of the present study was to investigate potential central mechanisms involved in the occlusal interference-induced facial hypersensitivity. A combination of behavioral, immunohistochemical, Western blot, and electrophysiological recording procedures was used in 98 male adult Sprague Dawley rats that either received the occlusal interference or were sham-operated or naive rats. Immunohistochemically labeled astrocytes and microglia in trigeminal subnucleus caudalis (Vc) showed morphological changes indicative of astrocyte and microglial activation after the occlusal interference. Prolonged upregulation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) was also documented in Vc after placement of the occlusal interference and was expressed in both neurons and glial cells at time points when rats showed peak mechanical facial hypersensitivity. The intrathecal administration of the p38 MAPK inhibitor SB203580 to the medulla significantly inhibited the occlusal interference-induced hypersensitivity, and the ERK inhibitor PD98059 produced an even stronger effect. Central sensitization of functionally identified Vc nociceptive neurons following placement of the occlusal interference was also documented by extracellular electrophysiological recordings, and intrathecal administration of PD98059 could reverse the neuronal central sensitization. These novel findings suggest that central mechanisms including central sensitization of trigeminal nociceptive neurons and non-neuronal processes involving MAPKs play significant roles in the production of occlusal interference-induced facial pain. PERSPECTIVE: Central mechanisms including trigeminal nociceptive neuronal sensitization, non-neuronal processes involving glial activation, and MAPKs play significant roles in occlusal interference-induced facial pain. These mechanisms may be involved in clinical manifestations of facial pain that have been reported in patients with an occlusal interference.

Asunto(s)

Sensibilización del Sistema Nervioso Central/fisiología , Oclusión Dental , Dolor Facial/enzimología , Dolor Facial/etiología , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Potenciales de Acción/efectos de los fármacos , Análisis de Varianza , Animales , Antígeno CD11b/metabolismo , Sensibilización del Sistema Nervioso Central/efectos de los fármacos , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Neuroglía/efectos de los fármacos , Nociceptores/efectos de los fármacos , Nociceptores/fisiología , Fosfopiruvato Hidratasa/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Núcleos del Trigémino/metabolismo

RESUMEN

The KA1 kainate receptor (KAR) subunit in the substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) has been implicated in the processing of nociceptive information from the orofacial region. This study compared the expression of the KA1 KAR subunit in the SG of the Vc in juvenile, prepubescent and adult mice. RT-PCR, Western blot and immunohistochemistry analyses were used to examine the expression level in SG area. The expression levels of the KA1 KAR subunit mRNA and protein were higher in juvenile mice than in prepubescent or adult mice. Quantitative data revealed that the KA1 KAR subunit mRNA and protein were expressed at levels approximately two and three times higher, respectively, in juvenile mice than in adult mice. A similar expression pattern of the KA1 KAR subunit was observed in an immunohistochemical study that showed higher expression in the juvenile (59%) than those of adult (35%) mice. These results show that the KA1 KAR subunits are expressed in the SG of the Vc in mice and that the expression level of the KA1 KAR subunit decreases gradually with postnatal development. These findings suggest that age-dependent KA1 KAR subunit expression can be a potential mechanism of age-dependent pain perception.

Asunto(s)

Animales , Ratones , Factores de Edad , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Receptores de Ácido Kaínico/metabolismo , Sustancia Gelatinosa/metabolismo