RESUMO
A set of fluorophenoxyanilides, designed to be simplified analogues of previously reported ω-conotoxin GVIA mimetics, were prepared and tested for N-type calcium channel inhibition in a SH-SY5Y neuroblastoma FLIPR assay. N-type or Cav2.2 channel is a validated target for the treatment of refractory chronic pain. Despite being significantly less complex than the originally designed mimetics, up to a seven-fold improvement in activity was observed.
Assuntos
Analgésicos não Narcóticos/farmacologia , Anilidas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/metabolismo , Desenho de Fármacos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Analgésicos não Narcóticos/síntese química , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/metabolismo , Anilidas/síntese química , Anilidas/química , Anilidas/metabolismo , Ligação Competitiva , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/metabolismo , Canais de Cálcio Tipo N/química , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular Tumoral , Fluorbenzenos/síntese química , Fluorbenzenos/química , Fluorbenzenos/metabolismo , Fluorbenzenos/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Estrutura Molecular , Terapia de Alvo Molecular , Proteínas do Tecido Nervoso/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Neurônios/metabolismo , Neurotoxinas/química , Dor Intratável/tratamento farmacológico , Dor Intratável/metabolismo , Relação Estrutura-Atividade , ômega-Conotoxina GVIA/química , ômega-Conotoxina GVIA/metabolismo , ômega-Conotoxina GVIA/farmacologiaRESUMO
Many pathological processes within the central nervous system are mediated by complex interactions between neurons and resident glial cells. In the case of painful peripheral neuropathy, spinal microglia react and undergo a series of changes that directly influence the establishment of neuropathic pain states. Purinergic signaling has been shown to be at the center of this reactivity, and here we review recent mechanistic advances describing the importance of microglial P2 receptors and their interactions with neuronal populations in the development of neuropathic pain.
Assuntos
Microglia/metabolismo , Dor Intratável/metabolismo , Receptores Purinérgicos P2/metabolismo , Animais , Humanos , Dor Intratável/genética , Dor Intratável/patologia , Receptores Purinérgicos P2/genética , Transdução de Sinais/genética , Medula Espinal/metabolismo , Medula Espinal/patologiaRESUMO
Noxious stimuli cause prompt phosphorylation of extracellular signal-regulated kinase (ERK) in the spinal dorsal horn that contributes to facilitation of pain sensation and is often used as an immediate marker for excitation of spinal neurons following somatic and colonic nociception. Here we asked whether two distinct pronociceptive stimuli with proteinase-activated receptor-2 (PAR2) agonists and hydrogen sulfide (H(2)S) in the pancreas cause phosphorylation of ERK in the spinal dorsal horn and also examined involvement of their possible downstream signaling molecules, transient receptor potential vanilloid-1 (TRPV1) and T-type Ca(2+) channels, respectively. Capsaicin (a TRPV1 agonist), trypsin (an endogenous PAR2 agonist), SLIGRL-NH(2) (a PAR2-activating peptide), and NaHS (an H(2)S donor) were infused into the pancreatic duct in anesthetized rats, and phosphorylated ERK in the spinal cord was detected by immunohistochemistry. Intraductal administration of capsaicin and trypsin caused prompt phosphorylation of ERK in the superficial layers of T9, but not T5 or T12, spinal dorsal horn. SLIGRL-NH(2) and NaHS, administered in the same manner, also produced ERK phosphorylation in the corresponding spinal regions. Mibefradil, a T-type Ca(2+) channel blocker, abolished the phosphorylation of ERK caused by intraductal NaHS but not SLIGRL-NH(2). In contrast, capsazepine, an inhibitor of TRPV1, suppressed the phosphorylation of ERK caused by intraductal SLIGRL-NH(2) but not NaHS. Our data thus demonstrate that pancreatic pronociceptive stimuli with PAR2 agonists and H(2)S cause ERK phosphorylation in the spinal dorsal horn, through activation of TRPV1 and T-type Ca(2+) channels, respectively, and that those two pronociceptive pathways are independent of each other.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sulfeto de Hidrogênio/toxicidade , Sistema de Sinalização das MAP Quinases/fisiologia , Nociceptores/metabolismo , Ductos Pancreáticos/metabolismo , Células do Corno Posterior/metabolismo , Receptor PAR-2/agonistas , Receptor PAR-2/fisiologia , Animais , Bloqueadores dos Canais de Cálcio/toxicidade , Capsaicina/análogos & derivados , Capsaicina/toxicidade , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Nociceptores/efeitos dos fármacos , Nociceptores/enzimologia , Dor Intratável/induzido quimicamente , Dor Intratável/tratamento farmacológico , Dor Intratável/metabolismo , Ductos Pancreáticos/efeitos dos fármacos , Ductos Pancreáticos/enzimologia , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Células do Corno Posterior/efeitos dos fármacos , Células do Corno Posterior/enzimologia , Ratos , Ratos WistarRESUMO
OBJECTIVE: To investigate the manifestation of ethology and the immunohistochemistry results of the 2B Subunits of N-methyl-D-aspartate receptors (NR2B) in the spinal cord dorsal horn and dorsal root ganglia (DRG) in mice with bone cancer pain and their correlation, and to discuss the role of NR2B in the generation and maintenance of bone cancer pain. METHODS: Forty-five male C57BL/6 mice were randomly divided into 3 groups: a model group (n=15), 2×10(6) cells in 10 µL D-Hank's were injected into the left femur of mice;a sham group(n=15), only 10 µL D-Hank's injected into the left femur of mice;and a normal control group(n=15), no treatment. Spontaneous lifting duration and mechanical withdrawal threshold of the hind paw of mice were measured on alternative days throughout the experiment. Bones from 5 mice in each group were stained with HE on Day 7, 15, and 23 after the inoculation and segments of lumbar spinal cord and L(4) DRG were taken to detect NR2B by immunohistochemistry. RESULTS: Bone cancer pain models were successfully established and confirmed by ethology and histology. The immunohistochemical positive indexes of NR2B were significantly higher in the model group than in the sham group and the control group. In the model group there were obvious differences either between Day 7 and Day 15, or between Day 7 and Day 23 (P<0.05). On Day 23, the immunohistochemical positive indexes of NR2B in the ipsilateral spinal cord dorsal horn of all groups, and L(4) DRG were positively correlated with the spontaneous lifting duration of ipsilateral hindpaw (r=0.976, P<0.001; r=0.882, P<0.001, respectively), negatively correlated with the mechanical withdrawal threshold of ipsilateral hindpaw (r=-0.879, P<0.001; r=-0.760, P=0.001, respectively). CONCLUSION: The immunohistochemical positive indexes of NR2B are increased and significantly correlated with the manifestation of ethology. NR2B in the spinal cord and L(4) DRG may participate and mediate in forming and developing hyperalgesia in bone cancer pain.
Assuntos
Neoplasias Ósseas/complicações , Gânglios Espinais/metabolismo , Dor Intratável/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Dor Intratável/etiologia , Distribuição Aleatória , Receptores de N-Metil-D-Aspartato/genéticaRESUMO
The midbrain periaqueductal grey (PAG) is a structure known for its roles in pain transmission and modulation. Noxious stimuli potentiate the glutamate synaptic transmission and enhance glutamate NMDA receptor expression in the PAG. However, little is known about roles of NMDA receptor subunits in the PAG in processing the persistent inflammatory pain. The present study was undertaken to investigate NR2A- and NR2B-containing NMDA receptors in the PAG and their modulation to the peripheral painful inflammation. Noxious stimuli induced by hind-paw injection of complete Freund's adjuvant (CFA) caused up-regulation of NR2B-containing NMDA receptors in the PAG, while NR2A-containing NMDA receptors were not altered. Whole-cell patch-clamp recordings revealed that NMDA receptor mediated mEPSCs were increased significantly in the PAG synapse during the chronic phases of inflammatory pain in mice. PAG local infusion of Ro 25-6981, an NR2B antagonist, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in rats. Hyperoside (Hyp), one of the flavonoids compound isolated from Rhododendron ponticum L., significantly reversed up-regulation of NR2B-containing NMDA receptors in the PAG and exhibited analgesic activities against persistent inflammatory stimuli in mice. Our findings provide strong evidence that up-regulation of NR2B-containing NMDA receptors in the PAG involves in the modulation to the peripheral persistent inflammatory pain.
Assuntos
Ácido Glutâmico/metabolismo , Inflamação/metabolismo , Dor Intratável/metabolismo , Substância Cinzenta Periaquedutal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Vias Aferentes/metabolismo , Vias Aferentes/fisiopatologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Doença Crônica , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Adjuvante de Freund , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nociceptores/metabolismo , Técnicas de Cultura de Órgãos , Medição da Dor/métodos , Dor Intratável/fisiopatologia , Técnicas de Patch-Clamp , Substância Cinzenta Periaquedutal/fisiopatologia , Fenóis/farmacologia , Piperidinas/farmacologia , Quercetina/análogos & derivados , Quercetina/farmacologia , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
Glial cells are known to have a large impact on neuropathic pain conditions. Within the spinal cord, microglia rapidly respond to peripheral nerve injury, resulting in central sensitization and ultimately in the onset of enhanced pain behaviour. Astroglia respond with a short delay and are thought to contribute to the early maintenance of neuropathic pain. Nevertheless, it is unknown whether the roles of these glial cell types can be influenced by the chronicity of the neuropathology. Here, the persistent responses of astroglia and microglia to peripheral nerve injury within central pain networks in the upper dorsal horn laminae were studied. At 12 weeks after complete sciatic nerve injury, upregulation of glial fibrillary acidic protein (GFAP), but not complement receptor-3, could be detected in laminae II and III. Moreover, it was found that neuropathic animals with a higher degree of mechanical allodynia had a lower intensity of GFAP expression in lamina II (substantia gelatinosa). From these data we conclude that the role of astroglial responses in mechanical allodynia after peripheral nerve injury may be less straightforward as previously thought. Although astroglia are known to play a pro-nociceptive role in early neuropathic pain states, this role may shift to anti-nociception in more chronic pain states.
Assuntos
Proteína Glial Fibrilar Ácida/metabolismo , Gliose/metabolismo , Hiperalgesia/metabolismo , Neuroglia/metabolismo , Dor Intratável/metabolismo , Substância Gelatinosa/metabolismo , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Biomarcadores/análise , Biomarcadores/metabolismo , Doença Crônica , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/análise , Gliose/etiologia , Gliose/fisiopatologia , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Imuno-Histoquímica , Masculino , Microglia/citologia , Microglia/metabolismo , Neuroglia/citologia , Dor Intratável/patologia , Dor Intratável/fisiopatologia , Células do Corno Posterior/citologia , Células do Corno Posterior/metabolismo , Ratos , Ratos Wistar , Receptores de Complemento/metabolismo , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia , Neuropatia Ciática/fisiopatologia , Substância Gelatinosa/patologia , Substância Gelatinosa/fisiopatologia , Regulação para Cima/fisiologiaRESUMO
OBJECTIVES: Electroconvulsive shock therapy (ECT) has been widely used as an effective and established treatment for refractory depression and schizophrenia. Some reports have shown that ECT is also effective for treating refractory neuropathic pain. DESIGN: In a rat model of neuropathic pain produced by chronic constrictive injury (CCI) of the sciatic nerve, thermal hyperalgesia, and mechanical allodynia were observed from day 2 after surgery. An electroconvulsive shock (ECS) was administered to rodents once daily for 6 days on days 7-12 after CCI operation using a pulse generator. Thermal and mechanical stimulation tests were performed to assess pain thresholds. Real-time polymerase chain reaction was used to measure the gene expression levels for 5HT(1A)R, 5HT(2A)R, neuropeptide Y (NPY), and GABAA(alpha1)R in the brain. RESULTS: After ECS, the latency to withdrawal from thermal stimulation was significantly increased; however, pain withdrawal thresholds in response to mechanical stimulation were not significantly changed. Expression ratios of NPY were significantly greater after ECS. CONCLUSION: Symptoms of neuropathic pain improved and expression of NPY in the brain was increased in CCI model rats after ECS, suggesting that changes in the expression of NPY in the brain may be related to the mechanism of action of ECT in treating neuropathic pain.
Assuntos
Química Encefálica/genética , Eletroconvulsoterapia , Neuropeptídeo Y/genética , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/terapia , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/fisiologia , Masculino , Neuropeptídeo Y/metabolismo , Medição da Dor , Limiar da Dor/fisiologia , Dor Intratável/genética , Dor Intratável/metabolismo , Dor Intratável/terapia , Doenças do Sistema Nervoso Periférico/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo de Reação/genética , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT2A de Serotonina/genética , Receptores de GABA-A/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neuropatia Ciática/genética , Neuropatia Ciática/metabolismo , Neuropatia Ciática/terapia , Serotonina/metabolismo , Transmissão Sináptica/genética , Regulação para Cima/genética , Ácido gama-Aminobutírico/metabolismoRESUMO
The role of water channel aquaporin 1 (AQP-1) in uninjured or injured spinal cords is unknown. AQP-1 is weakly expressed in neurons and gray matter astrocytes, and more so in white matter astrocytes in uninjured spinal cords, a novel finding. As reported before, AQP-1 is also present in ependymal cells, but most abundantly in small diameter sensory fibers of the dorsal horn. Rat contusion spinal cord injury (SCI) induced persistent and significant four- to eightfold increases in AQP-1 levels at the site of injury (T10) persisting up to 11 months post-contusion, a novel finding. Delayed AQP-1 increases were also found in cervical and lumbar segments, suggesting the spreading of AQP-1 changes over time after SCI. Given that the antioxidant melatonin significantly decreased SCI-induced AQP-1 increases and that hypoxia inducible factor-1alpha was increased in acutely and chronically injured spinal cords, we propose that chronic hypoxia contributes to persistent AQP-1 increases after SCI. Interestingly; AQP-1 levels were not affected by long-lasting hypertonicity that significantly increased astrocytic AQP-4, suggesting that the primary role of AQP-1 is not regulating isotonicity in spinal cords. Based on our results we propose possible novel roles for AQP-1 in the injured spinal cords: (i) in neuronal and astrocytic swelling, as AQP-1 was increased in all surviving neurons and reactive astrocytes after SCI and (ii) in the development of the neuropathic pain after SCI. We have shown that decreased AQP-1 in melatonin-treated SCI rats correlated with decreased AQP-1 immunolabeling in the dorsal horns sensory afferents, and with significantly decreased mechanical allodynia, suggesting a possible link between AQP-1 and chronic neuropathic pain after SCI.
Assuntos
Aquaporina 1/metabolismo , Edema/metabolismo , Hipóxia/metabolismo , Dor Intratável/metabolismo , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Vias Aferentes/metabolismo , Vias Aferentes/fisiopatologia , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Astrócitos/metabolismo , Tamanho Celular/efeitos dos fármacos , Doença Crônica , Modelos Animais de Doenças , Edema/etiologia , Edema/fisiopatologia , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Hipóxia/etiologia , Hipóxia/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Melatonina/metabolismo , Melatonina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Dor Intratável/etiologia , Dor Intratável/fisiopatologia , Células do Corno Posterior/metabolismo , Células do Corno Posterior/fisiopatologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Equilíbrio Hidroeletrolítico/fisiologiaRESUMO
In recent years a role for EphB receptor tyrosine kinases and their ephrinB ligands in activity-dependent synaptic plasticity in the CNS has been identified. The aim of the present study was to test the hypothesis that EphB receptor activation in the adult rat spinal cord is involved in synaptic plasticity and processing of nociceptive inputs, through modulation of the function of the glutamate ionotropic receptor NMDA (N-methyl-D-aspartate). In particular, EphB receptor activation would induce phosphorylation of the NR2B subunit of the NMDA receptor by a Src family non-receptor tyrosine kinase. Intrathecal administration of ephrinB2-Fc in adult rats, which can bind to and activate EphB receptors and induce behavioral thermal hyperalgesia, led to NR2B tyrosine phosphorylation, which could be blocked by the Src family kinase inhibitor PP2. Furthermore animals pre-treated with PP2 did not develop behavioral thermal hyperalgesia following EphrinB2-Fc administration, suggesting that this pathway is functionally significant. Indeed, EphB1-Fc administration, which competes with the endogenous receptor for ephrinB2 binding and prevents behavioral allodynia and hyperalgesia in the carrageenan model of inflammation, also inhibited NR2B phosphorylation in this model. Taken together these findings support the hypothesis that EphB-ephrinB interactions play an important role in NMDA-dependent, activity-dependent synaptic plasticity in the adult spinal cord, inducing the phosphorylation of the NR2B subunit of the receptor via Src family kinases, thus contributing to chronic pain states.
Assuntos
Efrina-B2/metabolismo , Hiperalgesia/metabolismo , Inflamação/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Tirosina/metabolismo , Quinases da Família src/metabolismo , Animais , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Carragenina/farmacologia , Efrina-B2/farmacologia , Ácido Glutâmico/metabolismo , Hiperalgesia/fisiopatologia , Inflamação/fisiopatologia , Mediadores da Inflamação/farmacologia , Masculino , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Nociceptores/metabolismo , Dor Intratável/metabolismo , Dor Intratável/fisiopatologia , Fosforilação/efeitos dos fármacos , Células do Corno Posterior/metabolismo , Células do Corno Posterior/fisiopatologia , Ratos , Ratos Wistar , Receptor EphB1/agonistas , Receptores da Família Eph/agonistas , Receptores da Família Eph/metabolismo , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Quinases da Família src/efeitos dos fármacosRESUMO
Sublingual buphrenorphine is a unique opioid medication based on its pharmacokinetics and pharmacodynamic properties. It may be used "on label" as an alternative choice to methadone for the treatment of opioid addiction or "off-label" for the treatment of both acute and chronic pain. Because of high mu receptor affinity and resultant blockade, it has been suggested that this might interfere with the management of moderate to severe pain in patients on opioid agonist treatment. The following article will offer strategies and approaches to address some of these real and perceived challenges.
Assuntos
Analgésicos Opioides/administração & dosagem , Buprenorfina/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Doença Aguda/terapia , Administração Sublingual , Adulto , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacocinética , Buprenorfina/efeitos adversos , Buprenorfina/farmacocinética , Doença Crônica/terapia , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/metabolismo , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Dor Intratável/tratamento farmacológico , Dor Intratável/metabolismo , Dor Intratável/fisiopatologia , Receptores Opioides/efeitos dos fármacos , Receptores Opioides/metabolismoRESUMO
OBJECTIVE: Protein-free extracts from the inflamed skin of rabbits inoculated with vaccinia virus (Rosemorgen and Neurotropin are widely employed to combat chronic pain and treat allergic conditions in human subjects in Japan. However, the pharmacologic mechanisms of Rosemorgen and Neurotropin remain unclear. METHODS: In this study, we examined the effects of Rosemorgen on L-glutamic acid (Glu)-induced cell death in N18-RE-105 neural cell line, which only possessed non-N-methyl-D-aspartate (NMDA)-type receptors. RESULTS: There were many large cytoplasmic cells and elongation of fivers in phosphate-buffered saline (PBS) additional group without Glu. In PBS and Glu simultaneous additional group, the survival ratio was decrease significantly compared with PBS alone group. Moreover, there were dead cells which did not have cytoplasm and aggregated nucleus. The Glu-induced cell death of N18-RE-105 cells was inhibited by both pre-treatment (24 hours before Glu treatment) and simultaneous treatment with Rosemorgen. There were many large cytoplasmic cells and elongation of fivers in Rosemorgen group. DISCUSSION: From this finding in N18-RE-105 cells, Rosemorgen was concluded to inhibit Glu-induced cell death via non-NMDA type receptors. One of the pharmacologic mechanisms of Rosemorgen has been clear. These results suggest that Rosemorgen depresses allodynia and chronic pain through interaction with non-NMDA type receptors.
Assuntos
Analgésicos/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Dor Intratável/tratamento farmacológico , Polissacarídeos/farmacologia , Receptores de Glutamato/efeitos dos fármacos , Extratos de Tecidos/farmacologia , Analgésicos/uso terapêutico , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Extratos Celulares/farmacologia , Extratos Celulares/uso terapêutico , Linhagem Celular Transformada , Forma do Núcleo Celular/efeitos dos fármacos , Forma do Núcleo Celular/fisiologia , Citoplasma/efeitos dos fármacos , Citoplasma/patologia , Dermatite/metabolismo , Dermatite/fisiopatologia , Dermatite/virologia , Ácido Glutâmico/toxicidade , Hibridomas , Camundongos , Degeneração Neural/tratamento farmacológico , Degeneração Neural/fisiopatologia , Degeneração Neural/prevenção & controle , Neurônios/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Neurotoxinas/antagonistas & inibidores , Neurotoxinas/toxicidade , Dor Intratável/metabolismo , Dor Intratável/fisiopatologia , Polissacarídeos/uso terapêutico , Coelhos , Ratos , Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Extratos de Tecidos/uso terapêutico , Vaccinia virus/imunologiaRESUMO
The lingual nerve, a peripheral branch of the trigeminal nerve, can be damaged during the surgical removal of lower third molar teeth. This damage can lead to the development of dysaesthesia, with some patients complaining of burning pain. We investigated the hypothesis that vanilloid receptor 1 (TRPV1), a transducer of noxious heat stimuli, was involved in the development of this burning pain. Neuroma specimens were obtained from patients undergoing microsurgical repair of a damaged lingual nerve. Repair was undertaken where there was little evidence of spontaneous recovery, 7-41 months after the initial injury. Preoperatively the incidence of dysaesthesia was determined by reported symptoms and using visual analogue scales (VAS) for pain, tingling and discomfort. Nine neuromas were studied from patients with burning dysaesthesia and six from patients with a sensory deficit but no dysaesthesia. Indirect immunofluorescence for protein gene product (PGP) 9.5 and TRPV1 was used to quantify the percentage area of PGP 9.5 positive neuronal tissue that also expressed TRPV1. The results showed no significant difference between the mean percentage area of TRPV1 expression in neuromas from patients with or without burning dysaesthesia. Furthermore, there was no correlation between TRPV1 expression and the VAS scores for pain, tingling or discomfort. However, if data from all patients was pooled, there was a negative correlation between the level of TRPV1 expression and the time after initial injury. These data do not rule out involvement of TRPV1 in the aetiology of burning dysaesthesia following lingual nerve injury but suggest that TRPV1 at the injury site does not play a primary role.
Assuntos
Traumatismos do Nervo Lingual , Nervo Lingual/metabolismo , Neuralgia/metabolismo , Neuroma/metabolismo , Canais de Cátion TRPV/metabolismo , Doenças do Nervo Trigêmeo/metabolismo , Adulto , Doença Crônica , Feminino , Humanos , Nervo Lingual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Dente Serotino/anatomia & histologia , Neuralgia/etiologia , Neuralgia/fisiopatologia , Neuroma/etiologia , Neuroma/fisiopatologia , Nociceptores/metabolismo , Procedimentos Cirúrgicos Bucais/efeitos adversos , Dor Intratável/etiologia , Dor Intratável/metabolismo , Dor Intratável/fisiopatologia , Parestesia/etiologia , Parestesia/metabolismo , Parestesia/fisiopatologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/fisiopatologia , Doenças do Nervo Trigêmeo/etiologia , Doenças do Nervo Trigêmeo/fisiopatologiaRESUMO
Using immunohistochemical methods we determined the presence of SP- and CGRP-immunopositive nerve fibers in the hip joint of patients with femoral neck fracture (controls, group 1), painful osteoarthritis (group 2), and painless failed total hip arthroplasties (group 3). Immunoreactive nerve fibers were found in the soft tissue of the fossa acetabuli as well as in the subintimal part of the synovial layer in the hip joint capsule of groups 1 and 2. In the capsule of controls the innervation density had a median of 5.7fibers/cm(2) for CGRP-ir and 3.2fibers/cm(2) for SP-ir afferents. In the osteoarthritic group, the density significantly increased to a median of 15.6fibers/cm(2) for CGRP-ir and 8.2fibers/cm(2) for SP-ir neurons (p=0.05). Patients with failed hip arthroplasties completely lacked these neuropeptide containing afferents. Innervation density in the fossa acetabuli of osteoarthritc patients showed a median of 14.1fibers/cm(2) for CGRP-ir and 5.9fibers/cm(2) for SP-ir afferents. From these data we assume that the hip joint capsule and the soft tissue of the fossa acetabuli are important triggers of nociception. This is supported by the fact, that patients with loosened total hip arthroplasties, where we failed to detect SP- and CGRP-immunoreactive fibers, did not feel pain. The upregulation of SP- and CGRP-positive neurons in response to arthritic stages suggests a mechanism involving neuropeptides in the maintenance of a painful degenerative joint disease and in mediating noxious stimuli from the periphery. Furthermore, these findings help to explain clinical observations, such as effectiveness of local therapy to control hip pain with intraarticular injection, synovectomy and denervation procedures.
Assuntos
Articulação do Quadril/inervação , Articulação do Quadril/fisiopatologia , Neuropeptídeos/metabolismo , Nociceptores/metabolismo , Osteoartrite do Quadril/fisiopatologia , Células Receptoras Sensoriais/metabolismo , Idoso , Artroplastia de Quadril/efeitos adversos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Nociceptores/citologia , Osteoartrite do Quadril/metabolismo , Dor/etiologia , Dor/fisiopatologia , Dor Intratável/etiologia , Dor Intratável/metabolismo , Dor Intratável/fisiopatologia , Complicações Pós-Operatórias/fisiopatologia , Células Receptoras Sensoriais/citologia , Substância P/metabolismo , Membrana Sinovial/inervação , Membrana Sinovial/fisiopatologia , Regulação para Cima/fisiologiaRESUMO
Tumor necrosis factor alpha (TNF-alpha) is implicated in the development of persistent pain. Its expression increases both spinally and supraspinally after peripheral inflammation. The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in pain transmission and modulation. Prefrontal synaptic transmission is potentiated in mice with chronic pain through an enhancement of presynaptic transmitter release. However, it is not known if TNF-alpha expression is altered in the ACC in response to persistent pain and if synaptic transmission within this region is modulated by TNF-alpha. In the present study, we examined TNF-alpha expression in the mouse ACC following hind-paw administration of complete Freund's adjuvant (CFA) and examined the role of TNF-alpha in ACC synaptic transmission. Quantification of TNF-alpha at the protein level (by ELISA) revealed enhanced expression following CFA-induced peripheral inflammation. In vitro whole-cell patch-clamp recordings revealed that TNF-alpha significantly enhanced synaptic transmission through increased probability of neurotransmitter release in the ACC. Our findings provide evidence that presynaptic alterations caused by peripheral inflammation is partly attributable to the up-regulation of TNF-alpha in the ACC.
Assuntos
Giro do Cíngulo/metabolismo , Inflamação/metabolismo , Dor Intratável/metabolismo , Córtex Pré-Frontal/metabolismo , Transmissão Sináptica/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Doença Crônica , Pé/inervação , Pé/fisiopatologia , Giro do Cíngulo/fisiopatologia , Inflamação/fisiopatologia , Mediadores da Inflamação/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neurotransmissores/metabolismo , Técnicas de Cultura de Órgãos , Dor Intratável/fisiopatologia , Técnicas de Patch-Clamp , Córtex Pré-Frontal/fisiopatologia , Terminações Pré-Sinápticas/metabolismo , Regulação para Cima/fisiologiaRESUMO
Pain pathways terminate in discrete brain areas that monitor the sensory and affective qualities of the initiating stimulus and show remarkable plasticity. Here, we found that chronic pain by sciatic nerve ligation caused a dramatic increase in glial fibrillary acidic protein (GFAP)-like immunoreactivity (IR), which is located in the dendritic astrocytes, with its expanding distribution in the cingulate cortex (CG) of mice. The branched GFAP-like IR in the CG of nerve-ligated mice was overlapped with S100beta-like IR, which is highly limited to the cell body of astrocytes, whereas there was no difference of S100beta-like IR between sham-operated and nerve-ligated mice. The number of BrdU-positive cells on the CG was not changed by sciatic nerve ligation. Furthermore, subventricular zone (SVZ)-derived neural stem cells marked by pEGFP-C1 did not migrate toward the CG after sciatic nerve ligation. In the behavioral assay, the thermal hyperalgesia observed on the ipsirateral side in nerve-ligated mice was significantly suppressed by a single pre-microinjection of a glial-modulating agent propentofylline into the CG 24 h before nerve ligation. These results suggest that chronic painful stimuli induces astrocyte activation in the CG, whereas they do not affect the cell proliferation/differentiation from neural stem cells in the CG and the migration of neural stem cells from the SVZ area. The astrocyte activation in the CG may, at least in part, contribute to the development of a chronic pain-like state following sciatic nerve ligation in mice.
Assuntos
Astrócitos/metabolismo , Diferenciação Celular/fisiologia , Gliose/fisiopatologia , Giro do Cíngulo/fisiopatologia , Dor Intratável/fisiopatologia , Células-Tronco/fisiologia , Animais , Astrócitos/citologia , Biomarcadores , Movimento Celular/fisiologia , Proliferação de Células , Células Cultivadas , Doença Crônica , Denervação , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/etiologia , Gliose/metabolismo , Giro do Cíngulo/citologia , Giro do Cíngulo/metabolismo , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/citologia , Neurônios/metabolismo , Dor Intratável/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/metabolismo , Neuropatia Ciática/complicações , Neuropatia Ciática/fisiopatologia , Transplante de Células-Tronco , Células-Tronco/citologiaRESUMO
Cancer, in general, is considered a disease of genetic mutation. Many questions are, however, unanswered. How exactly do mutations occur in the cells? How do gene mutations interface with the cell microenvironment and macroenvironment to create cancer phenotypes? Is mutation the cause of cancer or the consequence of special adaptive responses to aging; hormonal imbalance; physical, chemical and biologic stresses and damage? What makes cancer spread in the body and invade other organs causing death to the patient? In this paper, we hypothesize that the cellular hyperexcitability via stimulation of mineral channels (e.g. sodium voltage-gated channels) and ligand excitatory receptors (e.g. glutamate and other neuron and non-neuronal excitatory receptors) could be a significant causative and pathogenic factor of cancer. Managing hyperexcitatory states of the cells through lifestyle, nutritional changes, phytochemical and pharmaceutical medications theoretically could be a prospective direction in cancer prevention and therapy.
Assuntos
Transformação Celular Neoplásica , Neoplasias/etiologia , Neoplasias/metabolismo , Canais de Sódio/metabolismo , Anti-Infecciosos/farmacologia , Anticonvulsivantes/farmacologia , Antineoplásicos/farmacologia , Artemisia , Artemisininas/farmacologia , Morte Celular , Membrana Celular/metabolismo , Proliferação de Células , Humanos , Mutação , Neoplasias/genética , Dor Intratável/metabolismo , Fenitoína/farmacologia , Sesquiterpenos/farmacologiaRESUMO
The objective of the present work is to formulate 170Tm-EDTMP using an in-house freeze-dried EDTMP kit and evaluate its potential as a bone pain palliation agent. Patient dose of 170Tm-EDTMP was prepared with high radiochemical purity using the lyophilized kit at room temperature within 15min. Pre-clinical evaluation in normal Wistar rats revealed selective skeletal accumulation with extended retention. Preliminary clinical investigation in 8 patients with disseminated skeletal metastases exhibited selective uptake in the bone and retention therein for a long duration.
Assuntos
Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Osso e Ossos/metabolismo , Liofilização , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/farmacocinética , Organofosfonatos/administração & dosagem , Organofosfonatos/farmacocinética , Dor Intratável/tratamento farmacológico , Cuidados Paliativos/métodos , Idoso , Animais , Neoplasias Ósseas/complicações , Neoplasias Ósseas/diagnóstico por imagem , Osso e Ossos/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Animais , Dor Intratável/metabolismo , Ratos Wistar , Túlio/administração & dosagem , Túlio/farmacocinética , Distribuição TecidualRESUMO
UNLABELLED: Spinal glial activation and consequent interleukin-1 (IL-1) release are implicated in pain facilitation induced by inflammation/damage to skin and peripheral nerves. It is unclear whether pain facilitation induced at deep tissue sites also depends on these. We investigated whether spinal IL-1 and/or glial activation mediates bilateral allodynia induced by repeated unilateral intramuscular injections of acidic saline to rats. Given the prominent role of spinal IL-1 in various bilateral pain models, we predicted that intrathecal IL-1 receptor antagonist (IL-1ra) would suppress bilateral allodynia in this model as well. Surprisingly, neither single nor repeated intrathecal injections of IL-1ra affected allodynia, measured by the von Frey test, induced by prior intramuscular acidic saline compared with vehicle-injected controls. In addition, we tested the effect of 2 additional intrathecal manipulations that are broadly efficacious in suppressing glially mediated pain facilitation: (1) a glial metabolic inhibitor (fluorocitrate) and (2) the anti-inflammatory cytokine, interleukin-10 (IL-10). Like IL-1ra, fluorocitrate and IL-10 each failed to reverse allodynia. Finally, we observed no significant activation of glial cells, as assessed by immunohistochemistry of glial activation markers, in the lumbar spinal cord in response to intramuscular acidic saline. Taken together, the present data suggest that acidic saline-induced bilateral allodynia is created independently of glial activation. PERSPECTIVE: From converging lines of evidence, the current studies suggest that persistent bilateral allodynia induced by repeated intramuscular acidic saline is not mediated by spinal IL-1 and/or spinal glial activation. As such, this might represent the first evidence for pain facilitation occurring in the absence of glial involvement.
Assuntos
Gliose/metabolismo , Hiperalgesia/metabolismo , Interleucina-1beta/metabolismo , Neuroglia/metabolismo , Dor Intratável/metabolismo , Medula Espinal/metabolismo , Animais , Biomarcadores/metabolismo , Citratos/farmacologia , Modelos Animais de Doenças , Terapia Genética/métodos , Gliose/induzido quimicamente , Gliose/fisiopatologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Injeções Intramusculares/efeitos adversos , Injeções Espinhais , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-10/genética , Interleucina-10/farmacologia , Interleucina-1beta/imunologia , Interleucina-1beta/farmacologia , Masculino , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/imunologia , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Medição da Dor/efeitos dos fármacos , Dor Intratável/induzido quimicamente , Dor Intratável/fisiopatologia , Estimulação Física , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Cloreto de Sódio/efeitos adversos , Medula Espinal/imunologia , Medula Espinal/fisiopatologiaRESUMO
Endothelin-1 (ET-1) exists in endothelial cells as well as a variety of other cell types. The presence of ET-1 and its receptors in neurons suggests its possible role as a neurotransmitter and/or neuromodulator. Studies utilizing exogenous ET-1 have suggested that ET-1 affects pain transmission. This study was designed to examine the possible role(s) of neuronal ET-1 in pain processing. We produced neuron-specific ET-1 knockout mice using the Cre/loxP system with a synapsin I promoter and examined the effects produced by the lack of neuronal ET-1 on pain behavior using common pain models and a model of stress-induced analgesia. In acute nociceptive pain models, paw withdrawal thresholds to radiant heat and mechanical stimuli applied with von Frey hairs were significantly lower in the knockout mice compared with control. This indicated that the absence of neuronal ET-1 leads to greater sensitivity to acute nociceptive stimuli. After inflammation was produced by intraplantar injection of carrageenan, there was a significantly greater degree of thermal hyperalgesia and mechanical allodynia in the knockout mice even after the difference in baseline values was compensated. Furthermore, in a neuropathic pain model produced by spinal nerve ligation, there was also a greater degree of mechanical allodynia in the knockout mice. Finally, in a swim-stress model, the magnitude of stress-induced analgesia was less in the knockout mice, indicating the involvement of neuronal ET-1 in stress-induced analgesia. The results suggest that there is a basal release of ET-1 from neurons that affect baseline pain thresholds as well as an additional release during persistent pain states that acts to suppress the pain. The involvement of neuronal ET-1 in stress-induced analgesia further suggests its role in endogenous pain inhibitory systems. To confirm that ET-1 is released in persistent pain states and to determine which part of the CNS is involved, we measured the concentrations of ET-1 before and after inducing peripheral inflammation in different parts of the CNS involved in endogenous pain inhibitory systems in normal mice. We found that ET-1 was increased in the hypothalamus while no significant increase was observed in the midbrain, medulla and spinal cord. The results of the present study suggest that neuronal ET-1 is involved in endogenous pain inhibitory control likely via pathways through the hypothalamus.
Assuntos
Endotelina-1/genética , Hiperalgesia/genética , Hipotálamo/metabolismo , Vias Neurais/metabolismo , Limiar da Dor/fisiologia , Dor/genética , Doença Aguda , Animais , Modelos Animais de Doenças , Endotelina-1/deficiência , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Camundongos , Camundongos Knockout , Inibição Neural/fisiologia , Neurônios/metabolismo , Dor/metabolismo , Dor/fisiopatologia , Medição da Dor , Dor Intratável/genética , Dor Intratável/metabolismo , Dor Intratável/fisiopatologia , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/fisiopatologia , Estimulação Física , Regiões Promotoras Genéticas/genética , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Estresse Fisiológico/fisiopatologia , Sinapsinas/genéticaRESUMO
There are some reports regarding the inhibitory effect of pain on tolerance development to analgesic effect of opioids. The present study was designed to investigate whether the chronic formalin induced pain is able to reverse analgesic tolerance to morphine and to evaluate the expression of G(alpha i/o) and G(beta) subunits of G proteins in the context of chronic pain, development of morphine tolerance and their combination. Morphine tolerance was induced by chronic systemic (intraperitoneally, i.p.) or spinal (intrathecally, i.t.) administration of morphine to male Wistar rats weighing 200-240 g and analgesia was assessed using tail flick test. Chronic pain was induced by 4 daily intraplantar injections of 50 microl of 5% formalin. Lumbar spinal tissues were assayed for the expression of G(alpha i/o) and G(beta) proteins using "semiquantitative PCR" normalized to beta-actin gene expression. Results showed that chronic formalin induced pain could reduce and reverse the development of tolerance in rats that had received chronic (i.p. or i.t.) administration of morphine. Chronic administration of morphine did not change G(alpha i/o) gene expression, while chronic pain significantly increased its expression. The expression of G(beta), however, was increased after the chronic administration of morphine, but did not change after the induction of chronic pain. None of these increases were observed when morphine and formalin were administered at the same time. Due to synchronous development of morphine tolerance and changes in expression of G(beta), it may be concluded that the development of tolerance to analgesic effect of morphine is partially mediated by increase in G(beta) gene expression. The increase in G(alpha i/o) genes expression produced by chronic pain may facilitate the opioid signaling pathway and compensate for morphine-induced tolerance.