RESUMEN
ABSTRACT: The loss of GABAergic inhibition is a mechanism that underlies neuropathic pain. Therefore, rescuing the GABAergic inhibitory tone through the activation of GABA A receptors is a strategy to reduce neuropathic pain. This study was designed to elucidate the function of the spinal α 6 -containing GABA A receptor in physiological conditions and neuropathic pain in female and male rats. Results show that α 6 -containing GABA A receptor blockade or transient α 6 -containing GABA A receptor knockdown induces evoked hypersensitivity and spontaneous pain in naive female rats. The α 6 subunit is expressed in IB4 + and CGRP + primary afferent neurons in the rat spinal dorsal horn and dorsal root ganglia but not astrocytes. Nerve injury reduces α 6 subunit protein expression in the central terminals of the primary afferent neurons and dorsal root ganglia, whereas intrathecal administration of positive allosteric modulators of the α 6 -containing GABA A receptor reduces tactile allodynia and spontaneous nociceptive behaviors in female, but not male, neuropathic rats and mice. Overexpression of the spinal α 6 subunit reduces tactile allodynia and restores α 6 subunit expression in neuropathic rats. Positive allosteric modulators of the α 6 -containing GABA A receptor induces a greater antiallodynic effect in female rats and mice compared with male rats and mice. Finally, α 6 subunit is expressed in humans. This receptor is found in CGRP + and P2X3 + primary afferent fibers but not astrocytes in the human spinal dorsal horn. Our results suggest that the spinal α 6 -containing GABA A receptor has a sex-specific antinociceptive role in neuropathic pain, suggesting that this receptor may represent an interesting target to develop a novel treatment for neuropathic pain.
Asunto(s)
Neuralgia , Receptores de GABA-A , Masculino , Ratas , Femenino , Ratones , Humanos , Animales , Receptores de GABA-A/metabolismo , Hiperalgesia , Péptido Relacionado con Gen de Calcitonina/metabolismo , Asta Dorsal de la Médula Espinal/metabolismoRESUMEN
Chronic pain is an incapacitating condition that affects a large population worldwide. Until now, there is no drug treatment to relieve it. The impairment of GABAergic inhibition mediated by GABAA receptors (GABAA R) is considered a relevant factor in mediating chronic pain. Even though both synaptic and extrasynaptic GABAA inhibition are present in neurons that process nociceptive information, the latter is not considered relevant as a target for the development of pain treatments. In particular, the extrasynaptic α5 GABAA Rs are expressed in laminae I-II of the spinal cord neurons, sensory neurons, and motoneurons. In this review, we discuss evidence showing that blockade of the extrasynaptic α5 GABAA Rs reduces mechanical allodynia in various models of chronic pain and restores the associated loss of rate-dependent depression of the Hoffmann reflex. Furthermore, in healthy animals, extrasynaptic α5 GABAA R blockade induces both allodynia and hyperalgesia. These results indicate that this receptor may have an antinociceptive and pronociceptive role in healthy and chronic pain-affected animals, respectively. We propose a hypothesis to explain the relevant role of the extrasynaptic α5 GABAA Rs in the processing of nociceptive information. The data discussed here strongly suggest that this receptor could be a valid pharmacological target to treat chronic pain states.
Asunto(s)
Dolor Crónico/metabolismo , Receptores de GABA-A/metabolismo , Médula Espinal/metabolismo , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/fisiopatología , Antagonistas de Receptores de GABA-A/farmacología , Antagonistas de Receptores de GABA-A/uso terapéutico , Humanos , Nocicepción , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiopatologíaRESUMEN
Ceftriaxone (CFX) is a ß-lactam antibiotic with analgesic properties. However, its role in the formalin-induced nociception remains unknown. The purpose of this study was to investigate the antinociceptive effect of CFX in the 1% formalin test in rats. Formalin induced a typical nociceptive response (flinching behavior) of two phases. Local peripheral pretreatment (20 min) with CFX (400-800 µg/paw) slightly attenuated the flinching behavior in phase 2, but not phase 1. Acute intraperitoneal pretreatment (20 min) also reduced phase 2 of the formalin test. In both cases, CFX induced a dose-dependent antinociception. We also tested the effect of CFX 1 day after its administration and in two schedules of repeated administration. One-day pretreatment with CFX (50-400 mg/kg, ip) induced a dose-dependent antinociceptive effect in formalin-treated rats. Repeated administration (daily during 3 or 7 days) with CFX (50-400 mg/kg, ip) diminished formalin-induced nociception. Results suggest that local or systemic as well as single or repeated administration of CFX reduces formalin-induced nociception.
Asunto(s)
Analgésicos/administración & dosificación , Antibacterianos/administración & dosificación , Ceftriaxona/administración & dosificación , Nocicepción/efectos de los fármacos , Dolor/tratamiento farmacológico , Animales , Esquema de Medicación , Femenino , Formaldehído , Inyecciones Intraperitoneales , Dolor/inducido químicamente , Ratas WistarRESUMEN
Transcription factors are proteins that modulate the transcriptional rate of target genes in the nucleus in response to extracellular or cytoplasmic signals. Activating transcription factors 2 (ATF2) and 3 (ATF3) respond to environmental signals and maintain cellular homeostasis. There is evidence that inflammation and nerve injury modulate ATF2 and ATF3 expression. However, the function of these transcription factors in pain is unknown. The purpose of this study was to investigate the contribution of ATF2 and ATF3 to nerve injury-induced neuropathic pain. L5/6 spinal nerve ligation induced tactile allodynia and thermal hyperalgesia. Moreover, nerve damage enhanced ATF2 and ATF3 protein expression in injured L5/6 dorsal root ganglia and spinal cord but not in uninjured L4 dorsal root ganglia. Nerve damage also enhanced ATF2 immunoreactivity in dorsal root ganglia and spinal cord 7 to 21 days post-injury. Repeated intrathecal post-treatment with a small-interfering RNA targeted against ATF2 (ATF2 siRNA) or anti-ATF2 antibody partially reversed tactile allodynia and thermal hyperalgesia. In contrast, ATF3 siRNA or anti-ATF3 antibody did not modify nociceptive behaviors. ATF2 immunoreactivity was found in dorsal root ganglia and spinal cord co-labeling with NeuN mainly in non-peptidergic (IB4+) but also in peptidergic (CGRP+) neurons. ATF2 was found mainly in small- and medium-sized neurons. These results suggest that ATF2, but not ATF3, is found in strategic sites related to spinal nociceptive processing and participates in the maintenance of neuropathic pain in rats.
Asunto(s)
Factor de Transcripción Activador 2/metabolismo , Factor de Transcripción Activador 3/metabolismo , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Factor de Transcripción Activador 2/genética , Factor de Transcripción Activador 3/genética , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Modelos Animales de Enfermedad , Femenino , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Regulación de la Expresión Génica , Lectinas/metabolismo , Masculino , Microscopía Confocal , Dimensión del Dolor , Traumatismos de los Nervios Periféricos/complicaciones , Traumatismos de los Nervios Periféricos/patología , Fosfopiruvato Hidratasa/metabolismo , ARN Interferente Pequeño/administración & dosificación , Ratas , Ratas Wistar , Nervios Espinales/metabolismo , Nervios Espinales/patología , Tacto/fisiologíaRESUMEN
BACKGROUND: The amount of epicardial adipose tissue (EAT) around the heart has been identified as an independent predictor of coronary artery disease (CAD), potentially through local release of inflammatory cytokines. Ethnic differences have been observed, but no studies have investigated this relationship in the Mexican population. The objective of the present study was to evaluate whether a relationship exist between EAT thickness assessed via echocardiography with CAD and adiponectin levels in a Mexican population. METHODS: We studied 153 consecutive patients who underwent coronary angiography and transthoracic echocardiography (TTE). EAT thickness on the free wall of the right ventricle was measured at the end of systole from parasternal long and short axis views of three consecutive cardiac cycles. Coronary angiograms were analyzed for the presence, extent and severity of CAD. Serum adiponectin, lipids, glucose, C-reactive protein and fibrinogen were determined. RESULTS: EAT thickness was greater in patients with CAD than in those without CAD from both parasternal long (5.39 ± 1.75 mm vs 4.00 ± 1.67 mm p<0.0001) and short-axis views (5.23 ± 1.67 vs 4.12 ± 1.77, p=0.001). EAT thickness measured from parasternal long and short-axis showed a statistically significant positive correlation with age (r=0.354, p<0.001; r=0.286, p<0.001 respectively), and waist circumference (r=0.189, p=0.019; r=0.217, p=0.007 respectively). A significant negative correlation between EAT thickness from the parasternal long axis with cholesterol-HDL was observed (r=-0.163, p=0.045). No significant correlation was found between epicardial fat thickness and serum adiponectin or with the severity of CAD. CONCLUSIONS: EAT thickness was greater in patients with CAD. However, no correlation was observed with the severity of the disease or with serum adiponectin levels. EAT thickness measured by echocardiography might provide additional information for risk assessment and prediction of CAD.
Asunto(s)
Adiponectina/sangre , Tejido Adiposo/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/epidemiología , Pericardio/diagnóstico por imagen , Adiposidad , Biomarcadores/sangre , Causalidad , Comorbilidad , Enfermedad de la Arteria Coronaria/sangre , Femenino , Humanos , Incidencia , Masculino , México/epidemiología , Persona de Mediana Edad , Prevalencia , Reproducibilidad de los Resultados , Factores de Riesgo , Sensibilidad y Especificidad , UltrasonografíaRESUMEN
The macronutrient component of diets is critical for metabolic control and insulin action. The aim of this study was to compare the effects of high fat diets (HFDs) vs. high carbohydrate diets (HCDs) on metabolic control and insulin resistance in Wistar rats. Thirty animals divided into five groups (n = 6) were fed: (1) Control diet (CD); (2) High-saturated fat diet (HSFD); (3) High-unsaturated fat diet (HUFD); (4) High-digestible starch diet, (HDSD); and (5) High-resistant starch diet (HRSD) during eight weeks. HFDs and HCDs reduced weight gain in comparison with CD, however no statistical significance was reached. Calorie intake was similar in both HFDs and CD, but rats receiving HCDs showed higher calorie consumption than other groups, (p < 0.01). HRSD showed the lowest levels of serum and hepatic lipids. The HUFD induced the lowest fasting glycemia levels and HOMA-IR values. The HDSD group exhibited the highest insulin resistance and hepatic cholesterol content. In conclusion, HUFD exhibited the most beneficial effects on glycemic control meanwhile HRSD induced the highest reduction on lipid content and did not modify insulin sensitivity. In both groups, HFDs and HCDs, the diet constituents were more important factors than caloric intake for metabolic disturbance and insulin resistance.
Asunto(s)
Dieta Alta en Grasa , Carbohidratos de la Dieta/farmacología , Grasas de la Dieta/farmacología , Resistencia a la Insulina , Animales , Glucemia/análisis , Peso Corporal , Ingestión de Energía , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Metabolismo de los Lípidos , Masculino , Ratas , Ratas WistarRESUMEN
The effects of cholecystokinin (CCK-8) and the CCK receptor antagonist proglumide, on antinociception induced by local peripheral (subcutaneous) injected morphine in non-diabetic (ND) and streptozotocin-induced diabetic (D) rats, were examined by means of the formalin test. Morphine induced dose-dependent antinociception both in ND and D rats. However, in D rats, antinociceptive morphine potency was about twofold less than in ND rats. Pre-treatment with CCK-8 abolished the antinociceptive effect of morphine in a dose-dependent manner in both groups of rats. Additionally, proglumide enhanced the antinociceptive effect induced by all doses of morphine tested. Both CCK-8 and proglumide had no effect on flinching behaviour when given alone to ND rats. Unlike ND rats, in D rats proglumide produced dose-dependent antinociception and CCK-8 enhanced formalin-evoked flinches, as observed during the second phase of the test. In conclusion, our data show a decrease in peripheral antinociceptive potency of morphine when diabetes was present. Additionally, peripheral CCK plays an antagonic role to the peripheral antinociceptive effect of morphine, additional to the well known CCK/morphine interaction at spinal and supraspinal level.
Asunto(s)
Colecistoquinina/metabolismo , Morfina/uso terapéutico , Narcóticos/uso terapéutico , Neuralgia/tratamiento farmacológico , Animales , Área Bajo la Curva , Colecistoquinina/administración & dosificación , Colecistoquinina/antagonistas & inhibidores , Diabetes Mellitus Experimental/complicaciones , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Formaldehído/efectos adversos , Masculino , Neuralgia/etiología , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Fragmentos de Péptidos/administración & dosificación , Proglumida/administración & dosificación , Ratas , Ratas WistarRESUMEN
The possible pronociceptive role of peripheral cholecystokinin (CCK-8) as well as CCK(A) and CCK(B) receptors in diabetic rats was assessed. Subcutaneous injection of 0.5% formalin induced a greater nociceptive behavior in diabetic than in non-diabetic rats. Moreover, local peripheral injection of CCK-8 (0.1-100 microg) significantly increased 0.5% formalin-induced nociceptive activity in diabetic, but not in non-diabetic, rats. This effect was restricted to the formalin-injected paw as administration of CCK-8 into the contralateral paw was ineffective. Local peripheral administration of CCK-8, in the absence of formalin injection, produced a low level of, but significant increase in, flinching behavior in diabetic compared to non-diabetic rats. In addition, local peripheral administration of the non-selective CCK receptor antagonist proglumide (1-100 microg), CCK(A) receptor antagonist lorglumide (0.1-100 microg) or CCK(B) receptor antagonist CR-2945 (0.1-100 microg), but not vehicle or contralateral administration of CCK receptor antagonists, significantly reduced 0.5% formalin-induced flinching in diabetic rats. CR-2945 was the most effective drug in this condition. These effects were not observed in non-diabetic rats. The local peripheral pronociceptive effect of CCK-8 (100 microg) was significantly reduced by proglumide (100 microg), lorglumide (100 microg), and CR-2945 (100 microg). Results suggest that diabetes-induced peripheral sensitization could be due to a local peripheral release of CCK-8, which in turn would act on CCK(B), mainly but also in CCK(A), receptors located on the primary afferent neurons.
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Complicaciones de la Diabetes/fisiopatología , Hiperalgesia/fisiopatología , Umbral del Dolor/efectos de los fármacos , Receptor de Colecistoquinina A/metabolismo , Receptor de Colecistoquinina B/metabolismo , Sincalida/administración & dosificación , Sincalida/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Resistencia a Medicamentos , Formaldehído , Hiperalgesia/inducido químicamente , RatasAsunto(s)
Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Factor Natriurético Atrial/farmacología , GMP Cíclico/fisiología , Diclofenaco/farmacología , Óxido Nítrico/fisiología , Canales de Potasio/fisiología , Animales , Caribdotoxina/farmacología , GMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Femenino , Formaldehído , Gliburida/farmacología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico Sintasa/antagonistas & inhibidores , Oxadiazoles/farmacología , Dimensión del Dolor/efectos de los fármacos , Quinoxalinas/farmacología , Ratas , Ratas Wistar , Tolbutamida/farmacologíaRESUMEN
The peripheral antinociceptive effect of the selective COX-2 inhibitor celecoxib in the formalin-induced inflammatory pain was compared with that of resveratrol (COX-1 inhibitor) and diclofenac (non-selective COX inhibitor). Rats received local pretreatment with saline, celecoxib, diclofenac or resveratrol followed by 50 microl of either 1% or 5% formalin. Peripheral administration of celecoxib did not produce antinociception at either formalin concentration. In contrast, diclofenac and resveratrol produced a dose-dependent antinociceptive effect in the second phase of both 1% and 5% formalin test. The peripheral antinociception produced by diclofenac or resveratrol was due to a local action, as drug administration in the contralateral paw was ineffective. Results indicate that the selective COX-2 inhibitor celecoxib does not produce peripheral antinociception in formalin-induced inflammatory pain. In contrast, selective COX-1 and non-selective COX inhibitors (resveratrol and diclofenac, respectively) are effective drugs in this model of pain.
Asunto(s)
Analgesia , Antiinflamatorios no Esteroideos/uso terapéutico , Diclofenaco/uso terapéutico , Inflamación/fisiopatología , Estilbenos/uso terapéutico , Sulfonamidas/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Celecoxib , Inhibidores de la Ciclooxigenasa/uso terapéutico , Femenino , Formaldehído , Inflamación/inducido químicamente , Dolor/inducido químicamente , Pirazoles , Ratas , Ratas Wistar , ResveratrolRESUMEN
BACKGROUND: Lamotrigine inhibits glutamate release through the preferential blockade of voltage-dependent Na+ channels. In contrast, morphine reduces release of excitatory amino acids through the activation of opioid receptors and also inhibits tetrodotoxin-resistant Na+ channels on peripheral afferent neurons. The current study was designed to investigate the antinociceptive effects of locally administered morphine and lamotrigine. The interaction between morphine and lamotrigine at the periphery was also examined. METHODS: Morphine, lamotrigine, or a combination of morphine and lamotrigine was administered locally to female Wistar rats, and the antinociceptive effect was determined in the formalin test. Isobolographic analyses were used to define the nature of the functional interactions between morphine and lamotrigine. RESULTS: Peripheral administration of either morphine or lamotrigine produced a dose-related antinociceptive effect. Isobolographic analyses revealed that peripheral morphine and lamotrigine interacted synergistically in the formalin test. CONCLUSIONS: The study shows a functional interaction between lamotrigine and morphine at the peripheral level.
Asunto(s)
Analgésicos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Morfina/farmacología , Triazinas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Lamotrigina , Masculino , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
The involvement of K(+) channels in the antinociceptive action of diclofenac was assessed in the formalin test. Local administration of diclofenac produced a dose-dependent antinociceptive effect due to a local action because drug administration in the contralateral paw was ineffective. Pretreatment of the injured paw with glibenclamide and tolbutamide (ATP-sensitive K(+) channel inhibitors), charybdotoxin and apamin (large- and small-conductance Ca(2+)-activated K(+) channel blockers, respectively), 4-aminopyridine or tetraethylammonium (voltage-dependent K(+) channel inhibitors) prevented diclofenac-induced antinociception. Given alone, K(+) channel inhibitors did not modify formalin-induced nociceptive behavior. Pinacidil (an ATP-sensitive K(+) channel opener) also produced antinociception which was blocked by glibenclamide. The peripheral antinociceptive effect of morphine (positive control) was blocked by glibenclamide and 4-aminopyridine but not by charybdotoxin or apamin. The results suggest that the peripheral antinociceptive effect of diclofenac may result from the activation of several types of K(+) channels, which may cause hyperpolarization of peripheral terminals of primary afferents.