Alleviation of neuropathic pain by trazodone in rats

Abstract Neuropathic pain is generally characterised by an abnormal sensation (dysesthesia), an increased response to painful stimuli (hyperalgesia), and pain in response to a stimulus that does not normally provoke pain (allodynia). The present study was designed to investigate the effect of trazodone (5mg/kg and 10mg/kg) on peripheral neuropathic pain induced by partial sciatic nerve ligation in rats. Mechanical hyperalgesia, cold allodynia and thermal hyperalgesia were assessed by performing the pinprick, acetone, and hot plate tests, respectively. Biochemically, lipid peroxidation level and total calcium levels were measured. However, trazodone administration (5 and 10 mg/ kg i.p.) for 21days significantly diminished partial sciatic nerve ligation-induced neuropathic pain along with areduction in oxidative stress and calcium levels. The results of the present study suggest that trazodone is effective in attenuating partial sciatic nerve ligation-inducedpainful neuropathic states, which may be attributed to decreased oxidative stress and calcium levels.

The c-kit signaling pathway is involved in the development of persistent pain.

Protein kinase signal transduction pathways play critical roles in regulating nociception. Here we show that c-kit, a tyrosine kinase receptor, is expressed in lamina I and II layer of the dorsal horn. Moreover, the superficial c-kit(+) fibers originate from the dorsal root ganglion, and c-kit in lamina II inner layer comes from intrinsic expression of the spinal cord. Kit(W-v) mice, which contain a hypomorphic mutation, exhibited normal acute pain in most pain behavior tests. In the formalin test, the first phase was not affected, whereas the second phase pain response of Kit(W-v) mice was significantly reduced relative to wild-type littermates. Kit(W-v) mice also showed abnormal neuropathic pain, notably in the contralateral side of nerve injury. The expression and release of CGRP and substance P were not altered by the c-kit mutation. Together, these results implicate c-kit-mediated signal transduction in the development of persistent pain.

The effects of thalidomide and minocycline on taxol-induced hyperalgesia in rats.

Chemotherapy-induced pain is the most common treatment-limiting complication encountered by cancer patients receiving taxane-, vinca alkaloid- or platin-based chemotherapy. Several lines of evidence indicate that activation of pro-inflammatory cascades involving the release of cytokines including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and interleukin-6 (IL-6) as well as various growth factors are key events in the pathogenesis of many types of nerve-injury related pain. Similar mechanisms might also be involved in the etiology of chemotherapy-induced pain. Thalidomide and minocycline have profound immunomodulatory actions in addition to their originally intended pharmacological actions. These compounds were evaluated here for effects in preventing the development of taxol-induced mechanical and thermal hyperalgesia in rats. Thalidomide (50.0 mg/kg) reduced taxol-induced mechanical allodynia and hyperalgesia whereas minocycline (20.0 mg/kg) reduced taxol-induced mechanical hyperalgesia and allodynia as well as taxol-induced thermal hyperalgesia. These results suggest that immunomodulatory agents may provide a treatment option for the protection or reversal of chemotherapy-related pain.

Dolor y malestar: un ejemplo experimental de interacción neuro-inmune / Pain and sickness: an experimental example of neuro-immune interaction

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 off”y 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.

Interferência da idade e repetição de um estímulo nocivo na sensibilidade dolorosa em ratos / Interference of age and repetition of the same noxious stimulus on hyperalgesia in rats

Vários autores referem alterações da nocicepção após experiências anteriores. Avaliou-se resposta a estímulo agudo em ratos de 3, 6 e 9 meses, se a repetição de um estímulo influencia a expressão de hiperalgesia e dois métodos de indução de dor: injeção plantar de formol e incisão plantar. Ratos submetidos aos dois métodos, com hiperalgesia avaliada por filamentos de von Frey, demonstraram que, pela injeção de formol, jovens apresentam limiar menor de hiperalgesia em relação aos mais velhos, e que a repetição do mesmo estímulo diminui o limiar em jovens e aumenta em adultos e idosos. Pela incisão plantar, não houve diferenças estatisticamente significativas entre idades, mas sim entre as repetições. A comparação entre os métodos revelou que a incisão plantar produz maior hiperalgesia em relação à injeção de formol./Several authors propose nociceptive modification after previous experiences. The aims of this study was to compare response in 3, 6 and 9months old rats to an acute stimulus, if repetition of nociceptive stimulus influences hyperalgesia expression and plantar injection of formalin and plantar incision as inductors of hyperalgesia. Rats submitted to both methods and tested to hyperalgesia by von Frey filaments showed that with formol injection young rats express lower hyperalgesia thresholds than elder ones, and that repetition of same injury diminishes thresholds in young and augments it in elder rats. Plantar incision didn’t show differences among age groups, but among repetition trials. Comparison between methods revealed that plantar incision produces more hyperalgesia than formol injection...