RESUMEN
Dexamethasone is widely used in the therapy of chronic inflammatory diseases for its pain-modulating effects. The objective of this study was to evaluate the effect of dexamethasone on nociception and local inflammation, and the levels of brain-derived neurotrophic factor (BDNF) in the spinal cord in male rats with chronic inflammation induced by complete Freund's adjuvant (CFA). Rats were randomly divided into a control group (not manipulated) and 2 CFA-induced chronic inflammation groups (in the 15th post-CFA injection): 1 injected with vehicle (saline solution) and 1 received dexamethasone (0.25 mg/kg) for 8 days. The hot-plate and electronic von Frey tests were performed 24 h after the end of treatment. BDNF spinal cord levels were determined by enzyme-linked immunosorbent assay (ELISA). The level of inflammation in the tibiotarsal joint (the ankle region) was evaluated histologically at the end of treatment. Dexamethasone produced significantly increased latency in the hot-plate test (one-way ANOVA, p < 0.05) and withdrawal threshold in the electronic von Frey test (p < 0.005). The dexamethasone group showed increased spinal cord BDNF levels compared to the other groups (one-way ANOVA p, < 0.05). Histological analysis showed a local inflammatory response only in animals treated with vehicle, which demonstrated that the dexamethasone treatment decreased the inflammatory process. Our findings corroborate the antinociceptive and anti-inflammatory properties of dexamethasone. In addition, we showed that the dexamethasone treatment increased BDNF levels in the spinal cord; its pain- modulating effects can be attributed to this effect.
Asunto(s)
Antiinflamatorios/farmacología , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Dolor/líquido cefalorraquídeo , Animales , Enfermedad Crónica , Dexametasona/farmacología , Ensayo de Inmunoadsorción Enzimática , Adyuvante de Freund/toxicidad , Inflamación/líquido cefalorraquídeo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Masculino , Ratas , Ratas Wistar , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismoRESUMEN
This study analyzes the relationship between extracellular purines and pain perception in humans. Cerebrospinal fluid (CSF) levels of purines and their metabolites were compared between patients displaying acute and/or chronic pain syndromes and control subjects. The CSF levels of IMP, inosine, guanosine and uric acid were significantly increased in the chronic pain group and correlated with pain severity (P<0.05). Patients displaying both chronic and acute pain presented similar changes in the CSF purines concentration (P<0.05). However, in the acute pain group, only CSF inosine and uric acid levels were significantly increased (P<0.05). These findings suggest that purines, in special inosine, guanosine and uric acid, are associated with the spinal mechanisms underlying nociception.
Asunto(s)
Umbral del Dolor/fisiología , Dolor/líquido cefalorraquídeo , Dolor/psicología , Purinas/líquido cefalorraquídeo , Adolescente , Adulto , Anciano , Análisis de Varianza , Brasil , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor/métodos , Estudios Prospectivos , Estadística como Asunto , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: It is well known that adenine-based purines exert multiple effects on pain transmission. However, less attention has been given to the potential effects of guanine-based purines on pain transmission. The aim of this study was to investigate the effects of intraperitoneal (i.p.) and oral (p.o.) administration of guanosine on mice pain models. Additionally, investigation into the mechanisms of action of guanosine, its potential toxicity and cerebrospinal fluid (CSF) purine levels were also assessed. EXPERIMENTAL APPROACH: Mice received an i.p. or p.o. administration of vehicle (0.1 mM NaOH) or guanosine (up to 240 mg x kg(-1)) and were evaluated in several pain models. KEY RESULTS: Guanosine produced dose-dependent antinociceptive effects in the hot-plate, glutamate, capsaicin, formalin and acetic acid models, but it was ineffective in the tail-flick test. Additionally, guanosine produced a significant inhibition of biting behaviour induced by i.t. injection of glutamate, AMPA, kainate and trans-ACPD, but not against NMDA, substance P or capsaicin. The antinociceptive effects of guanosine were prevented by selective and non-selective adenosine receptor antagonists. Systemic administration of guanosine (120 mg x kg(-1)) induced an approximately sevenfold increase on CSF guanosine levels. Guanosine prevented the increase on spinal cord glutamate uptake induced by intraplantar capsaicin. CONCLUSIONS AND IMPLICATIONS: This study provides new evidence on the mechanism of action of the antinociceptive effects after systemic administration of guanosine. These effects seem to be related to the modulation of adenosine A(1) and A(2A) receptors and non-NMDA glutamate receptors.
Asunto(s)
Analgésicos/uso terapéutico , Guanosina/uso terapéutico , Dolor/tratamiento farmacológico , Administración Oral , Analgésicos/administración & dosificación , Analgésicos/líquido cefalorraquídeo , Analgésicos/farmacología , Analgésicos/toxicidad , Animales , Conducta Animal/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Edema/tratamiento farmacológico , Guanosina/administración & dosificación , Guanosina/líquido cefalorraquídeo , Guanosina/farmacología , Guanosina/toxicidad , Inyecciones Intraperitoneales , Dosificación Letal Mediana , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Dolor/líquido cefalorraquídeo , Dolor/fisiopatología , Umbral del Dolor/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismoRESUMEN
It is well known that adenine-based purines exert multiple effects on pain transmission. Recently, we have demonstrated that intracerebroventricular (i.c.v.) administered guanine-based purines are antinociceptive against chemical and thermal pain models in mice. The present study was designed to further investigate the antinociceptive effects of guanosine in mice. Animals received an intrathecal (i.t.) injection of vehicle (0.1 mN NaOH) or guanosine (10 to 400 nmol). Measurements of cerebrospinal fluid (CSF) purine levels and spinal cord glutamate uptake were performed. Guanosine produced dose-dependent antinociceptive effects against tail-flick, hot-plate, intraplantar (i.pl.) capsaicin, and i.pl. glutamate tests. Additionally, i.t. guanosine produced significant inhibition of the biting behavior induced by i.t. injection of glutamate (175 nmol/site), AMPA (135 pmol/site), kainate (110 pmol/site), trans-ACPD (50 nmol/site), and substance P (135 ng/site), with mean ID(50) values of 140 (103-190), 136 (100-185), 162 (133-196), 266 (153-461) and 28 (3-292) nmol, respectively. However, guanosine failed to affect the nociception induced by NMDA (450 pmol/site) and capsaicin (30 ng/site). Intrathecal administration of guanosine (200 nmol) induced an approximately 120-fold increase on CSF guanosine levels. Guanosine prevented the increase on spinal cord glutamate uptake induced by i.pl. capsaicin. This study provides new evidence on the mechanism of action of guanosine presenting antinociceptive effects at spinal sites. This effect seems to be at least partially associated with modulation of glutamatergic pathways by guanosine.