RESUMEN
BACKGROUND: Following peripheral nerve damage, various non-neuronal cells are activated, triggering accumulation in the peripheral and central nervous systems, and communicate with neurons. Evidence suggest that neuronal and non-neuronal cell communication is a critical mechanism of neuropathic pain; however, its detailed mechanisms in contributing to neuropathic orofacial pain development remain unclear. HIGHLIGHT: Neuronal and non-neuronal cell communication in the trigeminal ganglion (TG) is believed to cause neuronal hyperactivation following trigeminal nerve damage, resulting in neuropathic orofacial pain. Trigeminal nerve damage activates and accumulates non-neuronal cells, such as satellite cells and macrophages in the TG and microglia, astrocytes, and oligodendrocytes in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2). These non-neuronal cells release various molecules, contributing to the hyperactivation of TG, Vc, and C1-C2 nociceptive neurons. These hyperactive nociceptive neurons release molecules that enhance non-neuronal cell activation. This neuron and non-neuronal cell crosstalk causes hyperactivation of nociceptive neurons in the TG, Vc, and C1-C2. Here, we addressed previous and recent data on the contribution of neuronal and non-neuronal cell communication and its involvement in neuropathic orofacial pain development. CONCLUSION: Previous and recent data suggest that neuronal and non-neuronal cell communication in the TG, Vc, and C1-C2 is a key mechanism that causes neuropathic orofacial pain associated with trigeminal nerve damage.
Asunto(s)
Dolor Facial , Neuralgia , Dolor Facial/fisiopatología , Dolor Facial/patología , Neuralgia/fisiopatología , Neuralgia/patología , Humanos , Animales , Ganglio del Trigémino/patología , Comunicación Celular , Microglía/patología , Microglía/metabolismo , Astrocitos/patología , Macrófagos/metabolismo , Oligodendroglía/patología , Traumatismos del Nervio Trigémino/patología , Traumatismos del Nervio Trigémino/fisiopatología , Nociceptores/fisiología , Células Satélites Perineuronales/metabolismoRESUMEN
OBJECTIVE: Cancer-induced pain is the most common complication of the head and neck cancer. The microglia colony-stimulating factor receptor 1 (CSF1R) plays a crucial role in the inflammation and neuropathic pain. However, the effect of CSF1R on orofacial cancer-induced pain is unclear. Here, we aimed to determine the role of CSF1R in orofacial pain caused by cancer. METHODS: We established an animal model of cancer-induced orofacial pain with Walker 256B cells. Von Frey filament test and laser-intensity pain tester were used to evaluate tumor-induced mechanical and thermal hypersensitivity. Minocycline and PLX3397 were used to alter tumor-induced mechanical and thermal hyperalgesia. Additionally, we evaluated the effect of PLX3397 on immunoinflammatory mediators and neuronal activation within the trigeminal spinal subnucleus caudalis (Vc). RESULTS: Walker 256B cell-induced tumor growth resulted in mechanical and thermal hyperalgesia, accompanying by microglia activation and CSF1R upregulation. Treatment with minocycline or PLX3397 reversed the associated nocifensive behaviors and microglia activation triggered by tumor. As a result of PLX3397 treatment, tumor-induced increases in pro-inflammatory cytokine expression and neuronal activation of the Vc were significantly inhibited. CONCLUSIONS: The results of our study showed that blocking microglial activation via CSF1R may help prevent cancer-induced orofacial pain.
RESUMEN
Multiple animal models of migraine have been used to develop new therapies. Understanding the transition from episodic (EM) to chronic migraine (CM) is crucial. We established models mimicking EM and CM pain and assessed neuropathological differences. EM and CM models were induced with single NTG or multiple injections over 9 days. Mechanical hypersensitivity was assessed. Immunofluorescence utilized c-Fos, NeuN, and Iba1. Proinflammatory and anti-inflammatory markers were analyzed. Neuropeptides (CGRP, VIP, PACAP, and substance P) were assessed. Mechanical thresholds were similar. Notable neuropathological distinctions were observed in Sp5C and ACC. ACC showed increased c-Fos and NeuN expression in CM (p < 0.001) and unchanged in EM. Sp5C had higher c-Fos and NeuN expression in EM (p < 0.001). Iba1 was upregulated in Sp5C of EM and ACC of CM (p < 0.001). Proinflammatory markers were strongly expressed in Sp5C of EM and ACC of CM. CGRP expression was elevated in both regions and was higher in CM. VIP exhibited higher levels in the Sp5C of EM and ACC of CM, whereas PACAP and substance P were expressed in the Sp5C in both models. Despite similar thresholds, distinctive neuropathological differences in Sp5C and ACC between EM and CM models suggest a role in the EM to CM transformation.
Asunto(s)
Dolor Crónico , Trastornos Migrañosos , Animales , Ratones , Nitroglicerina/farmacología , Péptido Relacionado con Gen de Calcitonina/genética , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Sustancia P , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/genética , Modelos Animales de EnfermedadRESUMEN
Activation of microglia is known to be involved in neuropathic pain. However, the pathway that regulates the microglial activation is not completely understood. Transient receptor potential (TRP) melastatin 2 (TRPM2), which is part of the TRP superfamily, is reportedly expressed on microglia and is suggested to be involved in neuropathic pain. To explore the effect of a TRPM2 antagonist on orofacial neuropathic pain and the relationship between TRPM2 and the activation of microglia, experiments were conducted using male rats that underwent infraorbital nerve (ION) ligation as orofacial neuropathic pain models. TRPM2 expression was detected on microglia in the trigeminal spinal subnucleus caudalis (Vc). The immunoreactivity of TRPM2 in the Vc increased after ION ligation. Mechanical threshold for head-withdrawal response was measured using von Frey filament, and it decreased after ION ligation. When the TRPM2 antagonist was administered to the ION-ligated rats, the low mechanical threshold for head-withdrawal response increased, and the number of phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive cells in the Vc decreased. The number of CD68-immunoreactive cells in the Vc also decreased after the administration of the TRPM2 antagonist in the ION-ligated rats. These findings suggest that TRPM2 antagonist administration suppresses hypersensitivity to mechanical stimulation induced by ION ligation and microglial activation, and TRPM2 is also involved in microglial activation in orofacial neuropathic pain.
Asunto(s)
Neuralgia , Canales Catiónicos TRPM , Ratas , Masculino , Animales , Microglía/metabolismo , Canales Catiónicos TRPM/metabolismo , Neuralgia/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hiperalgesia/metabolismo , Modelos Animales de EnfermedadRESUMEN
Glial cells, such as microglia and astrocytes, in the trigeminal spinal subnucleus caudalis (Vc) are activated after trigeminal nerve injury and interact with Vc neurons to contribute to orofacial neuropathic pain. Complement C1q released from microglia has been reported to activate astrocytes and causes orofacial mechanical allodynia. However, how C1q-induced phenotypic alterations in Vc astrocytes are involved in orofacial pain remains to be elucidated. Intracisternal administration of C1q caused mechanical allodynia in the whisker pad skin and concurrent significant upregulation of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 in the Vc. Immunohistochemical analyses clarified that C1q induces a significant increase in the cytokine interleukin (IL)-1ß, predominantly in Vc astrocytes and partially in Vc microglia. The number of c-Fos-positive neurons in the Vc increased significantly in response to C1q. IL-1 receptor antagonist (IL-1Ra) was used to analyze the involvement of IL-1ß in C1q-induced mechanical allodynia. Intracisternal administration of IL-1Ra ameliorated C1q-induced orofacial mechanical allodynia. The present findings suggest that IL-1ß released from activated astrocytes and microglia in the Vc mediates C1q-induced orofacial pain.
Asunto(s)
Hiperalgesia , Microglía , Ratas , Animales , Hiperalgesia/metabolismo , Microglía/metabolismo , Astrocitos/metabolismo , Complemento C1q/metabolismo , Complemento C1q/farmacología , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Ratas Sprague-Dawley , Interleucina-1beta/metabolismo , Dolor Facial/metabolismoRESUMEN
A dopamine D2 receptor (D2R) agonist and an anti-calcitonin gene-related peptide (CGRP) antibody were separately reported to reduce neuropathic pain. To further attenuate neuropathic pain, co-administration of a D2R agonist and an anti-CGRP antibody was performed in a rat with the infraorbital nerve (ION) ligation. However, this co-administration showed no further attenuation of mechanical hypersensitivity compared to the administration of anti-CGRP antibody alone. Our results also revealed that D2R immunoreactivity in the trigeminal spinal subnucleus caudalis (Vc) increased following the nerve ligation and decreased following administration of an anti-CGRP antibody. The ratio of immunoreactive neurons of phosphorylated cyclic adenosine monophosphate-response-element-binding protein in the Vc also increased following nerve ligation and decreased with the anti-CGRP antibody. Our results suggest that a decrease in D2R immunoreactivity reduces the effect of a D2R agonist, and transcription of D2R is activated following the ION ligation and suppressed by treatment with an anti-CGRP antibody.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina , Neuralgia , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Neuronas/metabolismo , Ratas , Receptores de Dopamina D2/metabolismoRESUMEN
Orofacial neuropathic pain can cause considerable disruptions in patients' daily lives, especially because of a lack of effective medications as its underlying causative mechanisms are not fully understood. Here, we found neuron-specific expression of the interleukin (IL)-33 receptor in the trigeminal spinal subnucleus caudalis (Vc), distinct from the spinal dorsal horn. Reduction in head withdrawal threshold in response to von Frey filament stimulation of the whisker pad skin was inversely correlated with the upregulation of IL-33 in the Vc after infraorbital nerve injury (IONI). Neutralization of IL-33 in the Vc alleviated mechanical allodynia in the whisker pad skin after IONI; conversely, intracisternal administration of IL-33 elicited mechanical allodynia in the whisker pad skin, which was relieved by GluN2B antagonism. Moreover, IL-33 triggered the potentiation of GluN2B-containing N-methyl-D-aspartate receptor-mediated synaptic currents and phosphorylation of synaptosomal GluN2B in the Vc, whereas IONI-induced GluN2B phosphorylation was inhibited by neutralization of IL-33 in the Vc. IL-33-induced GluN2B phosphorylation was mediated by phosphorylation of Fyn kinase, and inhibition of the Fyn kinase pathway prevented the development of IL-33-induced mechanical allodynia. Our findings provide insights into a new mechanism by which IL-33 directly regulates synaptic transmission and suggest that IL-33 signaling could be a candidate target for therapeutic interventions for orofacial neuropathic pain.
Asunto(s)
Neuralgia , Receptores de N-Metil-D-Aspartato , Animales , Hiperalgesia/metabolismo , Interleucina-33/metabolismo , Neuralgia/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-fyn/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Currently, limited information regarding the role of calcitonin gene-related peptide (CGRP) in neuropathic pain is available. Intracerebroventricular administrations of an anti-CGRP antibody were performed in rats with infraorbital nerve ligation. Anti-CGRP antibody administration attenuated mechanical and heat hypersensitivities induced by nerve ligation and decreased the phosphorylated extracellular signal-regulated kinase expression levels in the trigeminal spinal subnucleus caudalis (Vc) following mechanical or heat stimulation. An increased CGRP immunoreactivity in the Vc appeared after nerve ligation. A decreased CGRP immunoreactivity resulted from anti-CGRP antibody administration. Our findings suggest that anti-CGRP antibody administration attenuates the symptoms of trigeminal neuropathic pain by acting on CGRP in the Vc.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Péptido Relacionado con Gen de Calcitonina/inmunología , Calor , Hipersensibilidad/prevención & control , Estrés Mecánico , Traumatismos del Nervio Trigémino/complicaciones , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Péptido Relacionado con Gen de Calcitonina/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hipersensibilidad/etiología , Inmunohistoquímica , Masculino , Microscopía Confocal , Neuralgia/etiología , Neuralgia/prevención & control , Fosforilación , Ratas Wistar , Núcleo Espinal del Trigémino/metabolismoRESUMEN
Trigeminal nerve injury is known to cause severe persistent pain in the orofacial region. This pain is difficult to diagnose and treat. Recently, many animal studies have reported that rewiring of the peripheral and central nervous systems, non-neuronal cell activation, and up- and down-regulation of various molecules in non-neuronal cells are involved in the development of this pain following trigeminal nerve injury. However, there are many unknown mechanisms underlying the persistent orofacial pain associated with trigeminal nerve injury. In this review, we address recent animal data regarding the involvement of various molecules in the communication of neuronal and non-neuronal cells and examine the possible involvement of ascending pathways in processing pathological orofacial pain. We also address the clinical observations of persistent orofacial pain associated with trigeminal nerve injury and clinical approaches to their diagnosis and treatment.
RESUMEN
While the descending dopaminergic control system is not fully understood, it is reported that the hypothalamic A11 nucleus is its principle source. To better understand the impact of this system, particularly the A11 nucleus, on neuropathic pain, we created a chronic constriction injury model of the infraorbital nerve (ION-CCI) in rats. ION-CCI rats received intraperitoneal administrations of quinpirole (a dopamine D2 receptor agonist). ION-CCI rats received microinjections of quinpirole, muscimol [a gamma-aminobutyric acid type A (GABAA) receptor agonist], or neurotoxin 6-hydroxydopamine (6-OHDA) into the A11 nucleus. A von Frey filament was used as a mechanical stimulus on the maxillary whisker pad skin; behavioral and immunohistochemical responses to the stimulation were assessed. After intraperitoneal administration of quinpirole and microinjection of quinpirole or muscimol, ION-CCI rats showed an increase in head-withdrawal thresholds and a decrease in the number of phosphorylated extracellular signal-regulated kinase (pERK) immunoreactive (pERK-IR) cells in the superficial layers of the trigeminal spinal subnucleus caudalis (Vc). Following 6-OHDA microinjection, ION-CCI rats showed a decrease in head-withdrawal thresholds and an increase in the number of pERK-IR cells in the Vc. Our findings suggest the descending dopaminergic control system is involved in the modulation of trigeminal neuropathic pain.
Asunto(s)
Nervios Craneales/metabolismo , Dopamina/metabolismo , Traumatismos del Nervio Facial/metabolismo , Animales , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Agonistas de Receptores de GABA-A/farmacología , Hiperalgesia/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Muscimol/farmacología , Neuralgia/metabolismo , Oxidopamina/farmacología , Dimensión del Dolor/métodos , Umbral del Dolor/fisiología , Fosforilación/efectos de los fármacos , Quinpirol/farmacología , Ratas , Ratas Wistar , Receptores de Dopamina D2/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Neuroplastic changes in the neuronal networks involving the trigeminal ganglion (TG), trigeminal spinal subnucleus caudalis (Vc), and upper cervical spinal cord (C1/C2) are considered the mechanisms underlying the ectopic orofacial hypersensitivity associated with trigeminal nerve injury or orofacial inflammation. It has been reported that peripheral nerve injury causes injury discharges in the TG neurons, and a barrage of action potentials is generated in TG neurons and conveyed to the Vc and C1/C2 after trigeminal nerve injury. Long after trigeminal nerve injury, various molecules are produced in the TG neurons, and these molecules are released from the soma of TG neurons and are transported to the central and peripheral terminals of TG neurons. These changes within the TG cause neuroplastic changes in TG neurons and they become sensitized. The neuronal activity of TG neurons is further accelerated, and Vc and C1/C2 neurons are also sensitized. In addition to this cascade, non-neuronal glial cells are also involved in the enhancement of the neuronal activity of TG, Vc, and C1/C2 neurons. Satellite glial cells and macrophages are activated in the TG after trigeminal nerve injury and orofacial inflammation. Microglial cells and astrocytes are also activated in the Vc and C1/C2 regions. It is considered that functional interaction between non-neuronal cells and neurons in the TG, Vc, and C1/C2 regions is a key mechanism involved in the enhancement of neuronal excitability after nerve injury or inflammation. In this article, the detailed mechanisms underlying ectopic orofacial hyperalgesia associated with trigeminal nerve injury and orofacial inflammation are addressed.
RESUMEN
The inferior alveolar nerve (IAN) comprises several types of sensory fibers. To clarify whether each type of primary afferent is regenerated comparably after injury, we developed a model of complete IAN transection (IANX) in mice. A retrograde tracer, fluoro-gold, injected into the mental skin was transferred to the cell bodies of a subset of isolectin B4 (IB4)-binding (non-peptidergic C) or CGRP-positive (peptidergic C) neurons at 2 weeks post-axotomy, indicating that the injured C afferents had regenerated anatomically. IANX led to a decrease of IB4-binding and CGRP immunoreactivity (IR) in the trigeminal ganglion (TG) and within the trigeminal spinal subnucleus caudalis (Vc) (i.e. terminals of the central branch of TG neurons). Two weeks after IANX, the reduction in IB4-binding activity and CGRP expression in the TG recovered to the control level; however, IB4-binding within the Vc did not, suggesting that central branch non-peptidergic neurons remained impaired. Two weeks after IANX, pinching or heat stimulus-induced extracellular signal-regulated kinase phosphorylation (pERK) was restored to the control level, but in the case of pinch stimulation the distribution pattern of pERK-IR cells was altered in the Vc. Taken together, our results support the possibility that peptidergic neurons regenerate more efficiently than non-peptidergic neurons after trigeminal nerve injury.
Asunto(s)
Regeneración Nerviosa/fisiología , Neuronas Aferentes/fisiología , Traumatismos del Nervio Trigémino , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , eIF-2 Quinasa/metabolismoRESUMEN
Although it is well known that migraine pain is enhanced by photic stimulation of the eye, the mechanisms underlying this response are not yet understood. Noxious stimulation to the dura is known to activate trigeminal spinal subnucleus caudalis and upper cervical spinal cord (Vc/C1) neurons, causing migraine pain. Intense photic stimulation to the eye is also known to activate certain Vc/C1 neurons, thus increasing migraine pain. In this study, we hypothesized that Vc/C1 neurons receiving noxious dural input would be further activated by intense photic stimulation, resulting in the enhancement of migraine pain. However, mechanisms underlying the interactions between dural and photic sensory information in Vc/C1 neurons is unknown. To evaluate the above hypothesis, we studied phosphorylated extracellular signal-regulated kinase (pERK) -immunoreactive (IR) cells in Vc/C1 in dural mustard oil (DMO)-administrated rats. The change in neuronal excitability of Vc/C1 nociceptive neurons receiving input from the dura in DMO rats was examined and tested if those neurons were modulated by intense flush light stimulation. There were many pERK-IR cells in the lateral portion of Vc/C1 after MO administration to the dura. Flashlight presentation to the eye in DMO rats caused an enhancement of ERK phosphorylation in Vc/C1 neurons and pERK-IR cells were significantly suppressed after intracisternal administration of MEK1 inhibitor PD98059. Dura-light sensitive (DL) neurons were recorded in the lateral portion of Vc/C1 and photic responses of DL neurons were significantly enhanced following dural MO administration. These findings indicate that DL Vc/C1 neurons in DMO rats intensified their responses to intense photic stimulation and that ERK phosphorylation in Vc/C1 neurons receiving noxious dural input increased with intense photic stimulation, suggesting that Vc/C1 nociceptive neurons are involved in the enhancement of dural nociception associated with intense light stimulation.
Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Luz , Trastornos Migrañosos/metabolismo , Neuronas/metabolismo , Médula Espinal/metabolismo , Núcleo Caudal del Trigémino/metabolismo , Animales , Masculino , Trastornos Migrañosos/patología , Planta de la Mostaza , Nociceptores/metabolismo , Fosforilación , Estimulación Luminosa , Aceites de Plantas/farmacología , Ratas Sprague-Dawley , Médula Espinal/patología , Médula Espinal/efectos de la radiación , Núcleo Caudal del Trigémino/patología , Núcleo Caudal del Trigémino/efectos de la radiaciónRESUMEN
In order to determine if the functional changes in the GABAergic system in the trigeminal spinal subnucleus caudalis (Vc) are involved in the mechanisms underlying extraterritorial neuropathic pain in the orofacial region following inferior alveolar nerve transection (IANX), mechanical noxious behavior, phosphorylated extracellular signal-regulated kinase (pERK) immunohistochemistry and single neuronal activity were analyzed in vesicular GABA transporter (VGAT)-VenusA rats expressing fluorescent protein and the VGAT in Vc neurons. The number of VGAT-VenusA positive neurons was significantly reduced in IANX rats than naive and sham rats at 7days after nerve transection. The number of VGAT-VenusA positive pERK-immunoreactive (IR) cells was significantly increased in IANX rats at 21days after IAN transection compared with naive and sham rats. The background activity and mechanical-evoked responses of Vc nociceptive neurons were significantly depressed after intrathecal application of the GABA receptor agonist muscimol in sham rats but not in IANX rats. Furthermore, the expression of potassium-chloride co-transporter 2 (KCC2) in the Vc was significantly reduced in IANX rats compared with sham rats. The head-withdrawal threshold (HWT) to mechanical stimulation of the whisker pad skin was significantly decreased in IANX rats compared with sham rats on days 7 and 21 after IANX. The significant reduction of the HWT and significant increase in the number of VGAT-VenusA negative pERK-IR cells were observed in KCC2 blocker R-DIOA-injected rats compared with vehicle-injected rats on day 21 after sham treatment. These findings revealed that GABAergic Vc neurons might be reduced in their number at the early period after IANX and the functional changes might occur in GABAergic neurons from inhibitory to excitatory at the late period after IANX, suggesting that the neuroplastic changes occur in the GABAergic neuronal network in the Vc due to morphological and functional changes at different time periods following IANX and resulting in the extraterritorial neuropathic pain in the orofacial region following trigeminal nerve injury.
Asunto(s)
Hiperalgesia/etiología , Bulbo Raquídeo/patología , Neuronas/fisiología , Umbral del Dolor/fisiología , Traumatismos del Nervio Trigémino/complicaciones , Ácido gamma-Aminobutírico/metabolismo , Acetatos/farmacología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Animales , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Agonistas de Receptores de GABA-A/farmacología , Proteína Ácida Fibrilar de la Glía/metabolismo , Indenos/farmacología , Nervio Mandibular/patología , Nervio Mandibular/cirugía , Muscimol/farmacología , Neuronas/efectos de los fármacos , Estimulación Física , Ratas , Ratas Transgénicas , Tiempo , Traumatismos del Nervio Trigémino/etiología , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/genética , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismoRESUMEN
It is commonly accepted that psychological stress contributes to the development of temporomandibular joint disorders, in which chronic orofacial pain is the main symptom. However, the central mechanism underlying the development of these disorders has remained unclear. The current study was performed to determine the involvement of the glia in the trigeminal spinal subnucleus caudalis in stress-induced increases in masseter muscle hyperalgesia in rats. After being subjected to chronic restraint stress, the animals showed decreased body weight gain, behavioral changes and marked masseter allodynia. We also found that astrocytes, but not microglia, in the trigeminal subnucleus caudalis (Vc) were dramatically activated. A further analysis was undertaken to investigate the contribution of the glia; we intrathecally injected l-α-aminoadipate (astrocyte-specific inhibitor) and/or minocycline (microglia-specific inhibitor) into the stressed rats. Our results showed that l-α-aminoadipate (LAA), but not minocycline, could significantly attenuate the mechanical masseter allodynia and behavioral changes induced by restraint stress. In addition, the expression of interleukin-1ß (IL-1ß) and phosphorylated N-methyl-d-aspartic acid receptor 1 (p-NR1) in the Vc was significantly increased after chronic restraint stress, whereas LAA dramatically inhibited the overexpression of IL-1ß and p-NR1. Taken together, these results suggest that activated astrocytes in the Vc may be one of the most important factors in the pathophysiology of masseter hyperalgesia induced by restraint stress and the following overexpression of IL-1ß and excessive NMDAR phosphorylation may ultimately contribute to masseter hyperalgesia. Thus, inhibiting spinal astrocytic activation may represent a novel therapeutic strategy for the treatment of orofacial pain induced by stress.
Asunto(s)
Astrocitos/fisiología , Hiperalgesia/fisiopatología , Músculo Masetero/fisiopatología , Estrés Psicológico/fisiopatología , Núcleo Espinal del Trigémino/fisiopatología , Adipatos/farmacología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Peso Corporal , Fármacos del Sistema Nervioso Central/farmacología , Enfermedad Crónica , Modelos Animales de Enfermedad , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/patología , Inyecciones Espinales , Interleucina-1beta/metabolismo , Masculino , Microglía/efectos de los fármacos , Microglía/patología , Microglía/fisiología , Minociclina/farmacología , Fosforilación/efectos de los fármacos , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Restricción Física , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/patología , Núcleo Espinal del Trigémino/efectos de los fármacos , Núcleo Espinal del Trigémino/patologíaRESUMEN
To investigate the neural mechanism of pain originating from the orofacial region in PD patients, we used PD model rats produced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. We investigated effects of nigrostriatal lesions on the behavioral response (face rubbing) to formalin injection into the upper lip. We also examined expression of c-Fos and phosphorylated extracellular signal-regulated kinase (pERK) in the trigeminal spinal subnucleus caudalis (Vc) and expression of c-Fos in the periaqueductal gray matter (PAG). Face rubbings following formalin injection showed a biphasic profile, with the first phase for the first 5 min and the second phase from 10 to 90 min. Rats with 6-OHDA lesions showed increased face rubbings in the second phase when formalin was injected ipsilaterally to the lesion, and c-Fos expression in the Vc increased. When formalin was injected contralaterally, face rubbings were reduced in the first phase, however, expression levels of c-Fos and pERK in the Vc were unchanged. No significant difference was found in c-Fos expression in the PAG between 6-OHDA- and saline-injected rats. These results suggest that unilateral dopamine depletion in the nigrostriatal pathway may be involved in hypersensitivity to noxious stimulation delivered to the orofacial region.
Asunto(s)
Dolor Facial/complicaciones , Hiperalgesia/etiología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dolor Facial/inducido químicamente , Formaldehído/toxicidad , Hiperalgesia/metabolismo , Masculino , Oxidopamina/toxicidad , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
A recent in vitro electrophysiological analysis combined with anatomical approach suggests that a potential disinhibitory mechanism involving somatostatin (SST), which is released by interneurons in the superficial dorsal horn, contributes to nociceptive transmission (Yasaka et al., 2010); however, whether this mechanism occurs in vivo remains to be determined. The aim of the present study was to investigate whether iontophoretic application of SST facilitates the excitability of nociceptive upper cervical spinal dorsal horn (C1) neurons through GABAergic disinhibiton, using extracellular electrophysiological recording with multibarrel electrodes and immunohistochemical techniques. Immunoreactivity of SST2A receptors was found in layer II of the C1 dorsal horn in the rat and most of these neurons co-expressed the GABA synthesizing enzyme glutamate decarboxylase 67. Single-unit recordings were made from C1 neurons responding to tooth-pulp (TP) electrical stimulation in pentobarbital anesthestized rats. Iontophoretic application of SST significantly increased TP-evoked C1 neuronal discharges in layers I and II of the spinal dorsal horn and this effect occurred in a current-dependent manner. The facilitation of this discharge by SST application was abolished with co-application of the SST2 receptor antagonist, Cyanamid 154806. Iontophoretic application of GABAA receptor antagonist, bicuculline, induced facilitation of TP-evoked C1 neuronal discharges. There was no significant difference in the relative number of spikes between SST and bicuculline applications. These results suggest that a local release of SST facilitates the excitability of trigeminal nocicepitve C1 neuronal activity via inhibition of GABAergic neurons. Therefore, SST2A receptors expressed in layer II GABAergic inhibitory interneurons play an important role in trigeminal nociceptive transmission and are a potential therapeutic target in the treatment of trigeminal pain, including hyperalgesia.