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Glial cell involvement in sensory nuclei participates in the development of neuropathic pain. Microglia and astroglia are activated and proliferated in the brainstem sensory nuclei of the trigeminal nerve. Increased primary afferent input following nerve injury causes the release of neurotransmitters and neural and immune mediators, which increase the sensitivity of postsynaptic secondary neurons and activate glial cells. Upon activation, glial cells release mediators (such as ATP, IL-1β, TNF-α and BDNF) that act on secondary neurons and increase their sensitivity. Glutamate–glutamine shuttle activity between astroglia and neurons is increased following nerve injury, thereby increasing the glutamate supply in the synapses between primary and secondary neurons. Cx43 expression increases in astroglia following trigeminal nerve injury, indicating increased communication among the astroglial cells. ATP: Adenosine triphosphate; CGRP: Calcitonin gene-related peptide; BDNF: Brain derived neurotrophic factor; IL-6: Interleukin 6; CCL2: Chemokine ligand 2; IL-1β: Interleukin 1 beta; TNF-α: Tumor necrosis factor alpha; A: Astroglia; M: Microglia.
Source publication
Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of inj...
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Background
Recently, we examined the effects of 2% lidocaine gel on the tactile sensory and pain thresholds of the face, tongue and hands of symptom-free individuals using quantitative sensory testing (QST); its effect was less on the skin of the face and hands than on the tongue. Consequently, instead of 2% lidocaine gel, we examined the effect of...
Citations
... Therefore, it is possible that penetration of a small amount of URB937 through the BBB at the area postrema level could have inhibited the activity of FAAH expressed by glial cells in the medulla [59][60][61]. This is also relevant when considering the importance of neuron-non-neuron interactions and glia-glia cross-talk in the development of peripheral and central sensitization [62][63][64] and in the maintenance of neuropathic pain [63,65,66]. Increased inflammatory mediators sensitize afferent nerves by changing the expression of ion channels, leading to spontaneous pain. ...
... Based on the available literature data, we hypothesize that following nerve injury, several signalling pathways occur at central and peripheral terminals during the development and maintenance of pain. These signalling mechanisms can activate both postsynaptic neurons and glia and increase neuron-glia coupling [66]. In our study, treatment with URB937 inhibited the development of allodynia but not its reversal, probably via an effect on the TG (acting directly on neurons and/or glial cells) that is not yet fully understood. ...
Cannabinoids are proposed for alleviating neuropathic pain, but their use is limited by cannabimimetic side effects. The inhibition of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the endocannabinoid anandamide, has received attention as an alternative to cannabinoids in the treatment of neuropathic pain. Here, we investigated the effect of URB937, a blood–brain barrier impermeant FAAH inhibitor, on experimentally induced mechanical allodynia in an animal model of trigeminal neuralgia. Male Sprague-Dawley rats were subjected to chronic constriction injury of the infraorbital nerve (IoN-CCI); operated animals were treated sub-chronically with URB937 (1 mg/kg, i.p.) or vehicle before or after trigeminal mechanical allodynia establishment. We also assayed mRNA expression levels of the pain neuropeptide calcitonin gene-related peptide (CGRP) and cytokines in the medulla, cervical spinal cord, and trigeminal ganglion ipsilateral to IoN-CCI using rt-PCR. URB937 treatment prevented the development of mechanical allodynia and IoN-CCI-induced changes in mRNA expression levels of CGRP and cytokines in the evaluated areas. When administered after allodynia development, URB937 prevented IoN-CCI-induced changes in CGRP and cytokine gene expression; this was not associated with a significant abrogation of the mechanical allodynia. These findings suggest that URB937 may counteract, but not reverse, the development of allodynia in trigeminal neuralgia. Further research is needed to elucidate the underlying mechanisms.
... Furthermore, besides the motor impairment per se, recent works have shown an increase in microglia and astrocytes in the Mo5 on trigeminal neuropathic pain models. In that way, the inhibition of microglial activity and attenuation of neuropathic pain behavior by microglial blockers suggest that microglial activity has a pathogenetic role also in orofacial motor dysfunction in neuropathic disease [39]. ...
... Further, injury to the facial and hypoglossal nerves also increases microglial activity in the motor nuclei of these nerves [40]. It is possible that similar to sensory nuclei, proinflammatory mediators, released by glial cells, modulate the excitability of motor neurons and thereby alter motor functions [39]. Considering that LID increases hyperalgesia in the present data, it is possible that the activation of glia in the facial nucleus may be explained not only by oral motor impairment but also by hypernociceptive behavior. ...
Parkinson’s Disease (PD), treated with the dopamine precursor l-3,4-dihydroxyphenylalanine (L-DOPA), displays motor and non-motor orofacial manifestations. We investigated the pathophysiologic mechanisms of the lateral pterygoid muscles (LPMs) and the trigeminal system related to PD-induced orofacial manifestations. A PD rat model was produced by unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. Abnormal involuntary movements (dyskinesia) and nociceptive responses were determined. We analyzed the immunodetection of Fos-B and microglia/astrocytes in trigeminal and facial nuclei and morphological markers in the LPMs. Hyperalgesia response was increased in hemiparkinsonian and dyskinetic rats. Hemiparkinsonism increased slow skeletal myosin fibers in the LPMs, while in the dyskinetic ones, these fibers decreased in the contralateral side of the lesion. Bilateral increased glycolytic metabolism and an inflammatory muscle profile were detected in dyskinetic rats. There was increased Fos-B expression in the spinal nucleus of lesioned rats and in the motor and facial nucleus in L-DOPA-induced dyskinetic rats in the contralateral side of the lesion. Glial cells were increased in the facial nucleus on the contralateral side of the lesion. Overall, spinal trigeminal nucleus activation may be associated with orofacial sensorial impairment in Parkinsonian rats, while a fatigue profile on LPMs is suggested in L-DOPA-induced dyskinesia when the motor and facial nucleus are activated.
... On the other hand, there is a growing amount of evidence that reveals an intra-ganglia capacity of "cross-talking" in sensory ganglia, based on the property of satellite glial cells and their neighboring neurons to have a crosstalk through an unknown chemical neuro-glio transmitter(s) (Suadicani et al. 2010;Christie et al. 2015;Retamal et al. 2017). This intercellular communication can potentially modulate the excitatory status of sensory neurons and, thus, the afferent discharge (Hanani 2010;Retamal et al. 2014b;Hossain et al. 2017;Yamakita et al. 2018). Recently, it has been shown that an increased neuronal activity induced by low extracellular calcium in the NG can be partly reversed by a P2X7 receptor blocker applied to the ganglion (Retamal et al. 2014a), suggesting a possible involvement of P2X7 receptors in the generation of neuronal activity. ...
Vagus nerve innervates several organs including the heart, stomach, and pancreas among others. Somas of sensory neurons that project through the vagal nerve are located in the nodose ganglion. The presence of purinergic receptors has been reported in neurons and satellite glial cells in several sensory ganglia. In the nodose ganglion, calcium depletion-induced increases in neuron activity can be partly reversed by P2X7 blockers applied directly into the ganglion. The later suggest a possible role of P2X7 receptors in the modulation of neuronal activity within this sensory ganglion. We aimed to characterize the response to P2X7 activation in nodose ganglion neurons under physiological conditions. Using an ex vivo preparation for electrophysiological recordings of the neural discharges of nodose ganglion neurons, we found that treatments with ATP induce transient neuronal activity increases. Also, we found a concentration-dependent increase in neural activity in response to Bz-ATP (ED50 = 0.62 mM, a selective P2X7 receptor agonist), with a clear desensitization pattern when applied every ~ 30 s. Electrophysiological recordings from isolated nodose ganglion neurons reveal no differences in the responses to Bz-ATP and ATP. Finally, we showed that the P2X7 receptor was expressed in the rat nodose ganglion, both in neurons and satellite glial cells. Additionally, a P2X7 receptor negative allosteric modulator decreased the duration of Bz-ATP-induced maximal responses without affecting their amplitude. Our results show the presence of functional P2X7 receptors under physiological conditions within the nodose ganglion of the rat, and suggest that ATP modulation of nodose ganglion activity may be in part mediated by the activation of P2X7 receptors.
... Sin embargo, en ambos estudios coincide la prevalencia de dolor muscular mayoritariamente en el sexo femenino. El dolor neuropático ocasiona absentismo laboral, alteración del estado anímico y afecta la calidad de vida del paciente, 9 por lo que es importante comprender su etiología para buscar el mejor tratamiento para el paciente. ...
... 12 El dolor neuropático se caracteriza por dolor espontáneo, ya sea continuo o episódico, y que se manifiesta como alodinia, es decir, estímulos que normalmente no provocarían dolor; e hiperalgesia, que son respuestas de dolor exageradas a estímulos nocivos. 9 Después de que se dañan los nervios trigéminos, alrededor de la neurona o del axón lesionado proliferan canales de sodio. Esto produce umbrales de estimulación más bajos y desencadenan la sensibilización central en el núcleo caudalis del trigémino, ocasionando dolor espontáneo e hipersensibilidad al dolor. ...
... La respuesta inmunitaria ante una lesión nerviosa tanto a nivel periférico como central, así como la activación, proliferación y señalización inflamatoria glial, son mecanismos importantes para el desarrollo y mantenimiento del dolor orofacial. 9,11 A nivel periférico, los nervios dañados y las células de Schwann liberan quimiocinas y citocinas, incluido el TNFα, IL-15 e IL-6, para facilitar el reclutamiento de macrófagos y la activación de los mastocitos y macrófagos residentes. El número de macrófagos en el sitio de una lesión del nervio espinal o una lesión del nervio trigémino se correlaciona positivamente con la alodinia. ...
El dolor, es definido como una experiencia sensitiva y emocional desagradable, asociada a una lesión tisular real o potencial. El dolor es uno de los principales motivos de consulta médica y en su forma crónica disminuye el estado anímico y la calidad de vida del paciente. Por esta razón, es indispensable para los profesionales de la salud, entender los mecanismos que lo producen. La mayoría de la información al respecto se basa en comprender cómo es que las neuronas reaccionan a los estímulos dolorosos y cómo esto se interpreta en el cerebro. Sin embargo, existen otras células del sistema nervioso que también intervienen en estos procesos. Estas son las células gliales, que incluye astrocitos, oligodendrocitos, microglía, células de Schwann y células gliales satélite. La presente revisión tiene por objetivo mostrar una recopilación de la función de las células gliales en los casos de dolor orofacial y la forma en la que se comunican con las neuronas y las células del sistema inmunitario para el desarrollo y mantenimiento del dolor.
... Sin embargo, en ambos estudios coincide la prevalencia de dolor muscular mayoritariamente en el sexo femenino. El dolor neuropático ocasiona absentismo laboral, alteración del estado anímico y afecta la calidad de vida del paciente, 9 por lo que es importante comprender su etiología para buscar el mejor tratamiento para el paciente. ...
... 12 El dolor neuropático se caracteriza por dolor espontáneo, ya sea continuo o episódico, y que se manifiesta como alodinia, es decir, estímulos que normalmente no provocarían dolor; e hiperalgesia, que son respuestas de dolor exageradas a estímulos nocivos. 9 Después de que se dañan los nervios trigéminos, alrededor de la neurona o del axón lesionado proliferan canales de sodio. Esto produce umbrales de estimulación más bajos y desencadenan la sensibilización central en el núcleo caudalis del trigémino, ocasionando dolor espontáneo e hipersensibilidad al dolor. ...
... 11,29 La comunicación intercelular entre las neuronas y las SGCS puede extenderse a las áreas circundantes, causando excitación cruzada a nivel del ganglio sensorial, lo que podría ser la base del dolor extraterritorial, produciendo hipersensibilidad ectópica. 9 Las SGCs son responsables de la homeostasis del K + perineuronal, regulada a través de canales específicos llamados Kir4.1 y uniones gap. Los niveles aumentados de K + se deben a un aumento de la excitabilidad de las neuronas, pudiendo conducir a alteraciones en la percepción sensorial. ...
El dolor, es definido como una experiencia sensitiva y emocional desagradable, asociada a una lesión tisular real o potencial. El dolor es uno de los principales motivos de consulta médica y en su forma crónica disminuye el estado anímico y la calidad de vida del paciente. Por esta razón, es indispensable para los profesionales de la salud, entender los mecanismos que lo producen. La mayoría de la información al respecto se basa en comprender cómo es que las neuronas reaccionan a los estímulos dolorosos y cómo esto se interpreta en el cerebro. Sin embargo, existen otras células del sistema nervioso que también intervienen en estos procesos. Estas son las células gliales, que incluye astrocitos, oligodendrocitos, microglía, células de Schwann y células gliales satélite. La presente revisión tiene por objetivo mostrar una recopilación de la función de las células gliales en los casos de dolor orofacial y la forma en la que se comunican con las neuronas y las células del sistema inmunitario para el desarrollo y mantenimiento del dolor.
Palabras clave: dolor orofacial, astrocitos, microglía, células gliales satélite, células de Schwann, dolor neuropático.
... Furthermore, excitation arising from the nerve fibers themselves can occur in the absence of nociceptors (i.e., ectopic excitation) where there is demyelination. This suggests that pain may occur even in the absence of stimulation, and that because the irritability of the nerve fiber endings increases, even mild tactile stimulation of the face may cause severe pain 15) . The dominant cause of demyelination is chronic compression, a form of mechanical stress, of the trigeminal neu-ron by cerebral arteries such as the superior cerebellar artery, anterior inferior cerebellar artery, or basilar artery 6) . ...
... Furthermore, these activities in both neurons and glial cells were suppressed by application of CBZ (Fig. 3). Neuron-glial interactions reportedly play an important role(s) in the development and/or mediation of chronic neuropathic pain 15) . Trigeminal neuralgia characteristically differs from chronic neuropathic pain, however. ...
Trigeminal neuralgia occurs in the orofacial region, characteristically causing pain that feels like a transient electric shock. Some histopathological studies have reported that trigeminal neuralgia is caused by mechanical compression of the demyelinated trigeminal nerve; the pathophysiological mechanism behind this phenomenon remains to be clarified, however. Cell-cell interactions have also been reported to be involved in the development and modulation of some types of neuropathic pain. The purpose of this study was to investigate the potential contribution of cell-cell interactions to trigeminal neuralgia by measuring intracellular free Ca2+ concentrations ([Ca2+]i) in primary cultured trigeminal ganglion (TG) cells. Direct mechanical stimulation of TG cells induced an increase in [Ca2+]i in both neuronal and non-neuronal cells, such as glial cells. Moreover, this increase was stimulus intensity-dependent and non-desensitizing. Direct mechanical stimulation increased [Ca2+]i in neighboring cells as well, and this increase was inhibited by application of carbamazepine. These results indicate that direct mechanical stimulation affects Ca2+ signaling. Trigeminal ganglion cells establish intercellular networks between themselves, suggesting that this is involved in the development and generation of trigeminal neuralgia.
... The infraorbital nerve of the wistar rat is a sensory nerve and is a branching of the trigeminal nerve. [25][26][27] Research conducted by Moldovan M et al. in 2006, shows that there is no difference in growth capacity in the neuroregeneration process both in the sensory nerve and in the motor nerve. 28 The infraorbital nerves in the facial area are easy to access so that they will provide convenience when carrying out experimental procedures. ...
Introduction
Chronic orofacial pain is associated with nerve tissues damage. Pharmacological therapy has limited therapeutic results because it is generally only symptomatic treatment. Neuroregeneration is a process which is needed to repair damaged of nerve tissue through healing or regrowth of nerve tissue. The survival of nerve cells need neurotrophic factors including Nerve Growth Factor (NGF) and S100B. High platelet concentrations in Platelet Rich Plasma contain of many trophic factors which play an important role in peripheral nerve regeneration following nerve injury. The aim of the present study is to analyze the increased expression of NGF and S100B following injection of Freeze-Dried Platelet Rich Plasma (FD-PRP) on axonotmesis injury.
Methods
Fifty-four male wistar rats aged 3 months randomly divided into 3 groups; negative control group (without nerve injury and without FD-PRP injection), positive control group (nerve injury but without FD-PRP injection) and treatment group (nerve injury and FD-PRP injection). Axonotmesis nerve injury created by clamping the infraorbital nerve for 15 seconds. Application of FD-PRP by injection technique. Examination of NGF and S100B expression was obtained by immunohistochemistry examination with monoclonal antibodies (anti-NGF and anti-S100B). Samples were taken on the 14th day and 21st day.
Results
Treatment group showed significant increase on both NGF and S100B compare to positive control (p = 0,000 and p = 0,000, respectively).
Conclusion
FD-PRP injection is effective in inducing neuroregeneration by increasing NGF and S100B expression.
... Reactive glial cells involve in central and peripheral sensitization [1,2,3,4]. In particular, microglia involves in the initiation and maintenance of neuropathic pain [1,2,4,5]. ...
... Reactive glial cells involve in central and peripheral sensitization [1,2,3,4]. In particular, microglia involves in the initiation and maintenance of neuropathic pain [1,2,4,5]. Several studies suggest that the endocannabinoid (eCB) system, an attractive target for managing microglial-mediated inflammation, may regulate many aspects of the central nervous system immune response [1,2,3,4,6]. ...
... In particular, microglia involves in the initiation and maintenance of neuropathic pain [1,2,4,5]. Several studies suggest that the endocannabinoid (eCB) system, an attractive target for managing microglial-mediated inflammation, may regulate many aspects of the central nervous system immune response [1,2,3,4,6]. ...
Endocannabinoids have an important role for the regulation of neuropathic pain. In our previous study, we observed that preventing the degradation of a endocannabinoid, 2-arachidonoylglycerol (2-AG), using an inhibitor of monoacylglycerol lipase (JZL184), attenuated neuropathic orofacial pain (NOP). The present study aimed to investigate mechanisms underlying JZL184-induced attenuation of NOP. We hypothesized that JZL184 may suppress microglial reactivity in the trigeminal spinal subnucleus caudalis (Vc) under NOP. The infraorbital nerve (ION) was hemisected to model NOP in mice, resulting in a significant reduction of mechanical head-withdrawal threshold (MHWT) on day 4 following the ION hemisection. Chronic systemic application of JZL184 at a concentration of 8 or 16 mg/kg/day for 4 days significantly attenuated the reduction of MHWT in mice exposed to NOP. Administering JZL184 at 4 mg/kg/day or its vehicle, however, did not attenuate the MHWT of mice with NOP. The reactivity of microglial cells in the Vc increased in mice with NOP compared to sham-operated controls. The application of JZL184 at 8 or 16 mg/kg/day for 4 days significantly reduced the increased microglial reactivity in the Vc. The changes of microglia under NOP were, by contrast, not reduced by application of the drug at 4 mg/kg/day or its vehicle. The results indicate that preventing 2-AG degradation may increase its accumulation in the Vc and normalize microglial reactivity under NOP, which may contribute to suppressing NOP.
... Central sensitization (CS) is a possible cause of the transition from acute to chronic pain. 1 CS is clinically characterized by disproportionate pain, in which the severity of pain and functional disability are disproportionate to detectable tissue damage and pathophysiology, or which occurs regardless of peripheral lesions. 2 CS has been defined as "an amplification of neural signaling within the central nervous system that elicits pain hypersensitivity." 3 Altered brain and brainstem function in the pain processing system corresponds to CS, including functional connectivity changes among brain regions, 4 neural plasticity, such as new synapse formation 5 and long-term potentiation, 6 imbalance of the activity between excitatory and inhibitory neurons, 7 and excess glial cell activation. 8 To evaluate CS, neurophysiological examinations (quantitative sensory testing, and various stimuli), 9 questionnaires, 10 functional magnetic resonance imaging (fMRI), and cerebral metabolite measurement (proton magnetic resonance spectroscopy: 1 H-MRS) have been used in medical practice and research. ...
Background
Refractory chronic pain in the orofacial region involves central sensitization (CS). However, not all chronic pain patients exhibit CS. An objective assessment of CS may be useful for pain management. Changes in the balance of excitatory and inhibitory neural activity or excessive activity of nerves and glial cells may cause CS and contribute to pain chronification.
Patients and Methods
¹H-magnetic resonance spectra were acquired from the anterior cingulate cortex (ACC) and thalamus in 20 patients with chronic orofacial pain and suspected CS, and 21 healthy volunteers, using a single-voxel point-resolved spectroscopy sequence. The patients were assessed using the Central Sensitization Inventory.
Results
Aspartate/total creatine (tCr) and glutathione in the ACC were significantly higher in the patient group. However, no significant difference was observed between groups in the neurometabolites measured in the thalamus. Patients also exhibited a tendency for increased gamma-aminobutyric acid (GABA)/tCr in the ACC. There were positive relationships between Central Sensitization Inventory scores and glutamate + glutamine (Glx) in the thalamus, a positive trend for Glx in the ACC and a negative relationship for GABA/tCr in the ACC.
Conclusion
The high levels of aspartate/tCr and glutathione in the patient group suggest excitatory neuronal activity and hyperactivity of neurons and glial cells. The correlation analysis results suggest that excitatory and inhibitory neurometabolites are involved in the chronification of orofacial pain, including CS.
... This process can increase paracrine signaling and cell sensitization mediated by the activation of purinergic receptors. Such activation might increase the intracellular calcium levels, facilitating an increase in neural activity (37). ...
Evidence has been reported that shows that somatosensory perception
can be altered by a trigeminal injury resulting from maxillofacial surgical procedures.
However, the surgical procedures that most frequently cause trigeminal lesions and
the risk factors are unknown. In the same way, there is little information on what
has been determined in preclinical models of trigeminal injury. This article integrates
relevant information on trigeminal injury from both clinical findings and primary basic
science studies. This review shows that the age and complexity of surgical procedures
are essential to induce orofacial sensory alterations.
