RESUMO
Current evidence suggests that activation of glial and immune cells leads to increased production of proinflammatory mediators, creating a neuroinflammatory state. Neuroinflammation has been proven to be a fundamental mechanism in the genesis of acute pain and its transition to neuropathic and chronic pain. A noxious event that stimulates peripheral afferent nerve fibers may also activate pronociceptive receptors situated at the dorsal root ganglion and dorsal horn of the spinal cord, as well as peripheral glial cells, setting off the so-called peripheral sensitization and spreading neuroinflammation to the brain. Once activated, microglia produce cytokines, chemokines, and neuropeptides that can increase the sensitivity and firing properties of second-order neurons, upregulating the signaling of nociceptive information to the cerebral cortex. This process, known as central sensitization, is crucial for chronification of acute pain. Immune-neuronal interactions are also implicated in the lesser-known complex regulatory relationship between pain and opioids. Current evidence suggests that activated immune and glial cells can alter neuronal function, induce, and maintain pathological pain, and disrupt the analgesic effects of opioid drugs by contributing to the development of tolerance and dependence, even causing paradoxical hyperalgesia. Such alterations may occur when the neuronal environment is impacted by trauma, inflammation, and immune-derived molecules, or when opioids induce proinflammatory glial activation. Hence, understanding these intricate interactions may help in managing pain signaling and opioid efficacy beyond the classical pharmacological approach.
RESUMO
El dolor neuropático es un síndrome de muy difícil manejo en la práctica clínica. Suele originarse a consecuencia de lesiones o enfermedades que afectan al sistema somatosensorial. Lesiones de nervios periféricos, la diabetes, el virus herpes zoster, entre otras, son ejemplos de entidades clínicas que causan dolor neuropático. Este tipo de dolor supone modificaciones de la fisiología normal de las neuronas que integran la vía de transmisión nociceptiva y que operan tanto a nivel periférico, como central. Entre estos mecanismos se incluye la generación de descargas ectópicas, cambios en el genoma de las neuronas involucradas, alteración de canales iónicos, pérdida de las actividades inhibitorias endógenas, activación anormal del sistema inmunitario y sensibilización tanto periférica, como central. Este artículo resume los mecanismos moleculares y neuroplásticos que ocurren en situaciones de dolor neuropático y revisa diferentes modelos experimentales para su estudio. El desarrollo de estos modelos ha permitido dilucidar los mecanismos subyacentes de esta patología, el diseño de nuevas estrategias terapéuticas y el diagnóstico acertado de la enfermedad
Neuropathic pain is a very complex clinical syndrome that results as a consequence of lesions or diseases affecting the somatosensory system. Lesion of peripheral nerves, diabetes, herpes zoster virus, among others, are clinical entities that may cause neuropathic pain. Neuropathic pain also reflects changes of the normal physiology of the nociceptive transmission neurons that may happen at peripheral and central levels. These mechanisms include the generation of ectopic discharges, genomic changes of the neurons involved, alterations of ionic channels and of the endogenous inhibition of pain, abnormal activation of the immune system as well as peripheral and central sensitization. This article review the molecular and neuroplastic mechanisms associated to neuropathic pain and discuss different experimental models for its study. The development of these models has been helpful to understand the subjacent mechanisms of this pathology, and has contributed to design new therapeutical approaches and the correct diagnose of the disease
Assuntos
Feminino , Inflamação , Manejo da Dor , Medição da Dor , Analgésicos/administração & dosagemRESUMO
Bajo la definición de malestar general se agrupan una constelación de signos y síntomas tales como fiebre, disminución de la actividad, pérdida del apetito, disminución de la libido, trastornos del sueño y modificaciones en el umbral del dolor, entre otros. Estas manifestaciones son necesarias para hacer frente a procesos infecciosos y son iniciadas por el sistema inmunitario y controladas por el sistema nervioso, por lo que representan un ejemplo ideal de interacción entre ambos componentes. En el presente estudio se analizaron los cambios conductuales inducidos en el umbral del dolor luego de la administración i.p. de lipopolisacárido (LPS), una endotoxina que forma parte de la pared de bacterias gram negativas. Adicionalmente, se determinaron los cambios que ocurren en los patrones de descarga de dos poblaciones de neuronas de la formación reticular bulbar, las células off y on, luego de la administración de la endotoxina. Estas células aparentemente constituyen los brazos ejecutores del sistema de modulación endógena del dolor. Los resultados obtenidos indican que dependiendo de la dosis de LPS empleada (100 o 200 μg/kg) se pueden activar diferentes mecanismos de modulación, que a su vez parecen depender de las dos poblaciones de neuronas bulbares. La dosis de 100 μg/kg de LPS produjo antinocicepción, la cual estuvo asociada a incrementos en la actividad de las células off y a la disminución de la actividad de las on. La dosis de 200 μg/kg de LPS produjo hiperalgesia, la cual se acompañó de una disminución de la actividad de las celulas offy un aumento en la actividad de las células on.
The definition of sickness/illness behavior involves a constellation of signs and symptoms such as fever, decrease of physical activity, anorexia, decrease of libido, insomnia and changes of the pain threshold, among others. These manifestations are necessary to face infectious processes and are apparently initiated and controlled by the immune and the nervous system, so that they represent an ideal example of interaction between both components. In the present study the behavioral changes in the pain threshold induced by the i.p. administration of lipopolysaccharide, an endotoxin derived from gram-negative bacterial cell walls, were analyzed. Additionally, changes in the discharge pattern of two neuronal populations of the medullary reticular formation, the off- and on-cells, which apparently act as the executory arm of the endogenous pain modulatory system were determined after endotoxin administration. The results indicate that depending on the LPS dose (100 or 200 μg/kg) different modulatory mechanisms might be activated, which in turn seem to be the consequence of the activation of the two different classes of medullary neurons. Antinociception was produced after administration of 100 μg/kg of LPS. That was associated to an increase of the off-cell firing and a reduction of the on-cell activity. Hyperalgesia was produced after administration of 200 μg/kg of LPS. That effect was accompanied by an inhibition of the off-cell activity and an increase of the on-cell firing. These findings suggest that changes of the pain threshold that occur during sickness/illness involve the differential participation of the two control options of the endogenous pain modulatory system and of specialized mechanisms of communication between the immune and the nervous system.