RESUMEN
Despite the importance of spinal metabotropic glutamate receptors (mGluRs) and opioid receptors in nociceptive processing, the roles of these receptors in the modulation of neuropathic pain at the spinal level have not been thoroughly investigated. The purpose of this study was to investigate the effects of spinal mGluR agents and opioids (morphine) on neuropathic pain. Male Sprague-Dawley rats underwent L5 and L6 spinal nerve ligation to induce neuropathic pain and intrathecal catheterization for drug administration. A paw-withdrawal threshold to mechanical stimulus was measured using the "up and down" method. When administered intrathecally, neither Group I mGluR antagonists nor Group II or III agonists modified the withdrawal threshold after spinal nerve ligation. Intrathecal administration of morphine dose-dependently increased the withdrawal threshold. Whereas ACPT-III, a Group III mGluR agonist, enhanced the antiallodynic action of morphine, other mGluR agents did not. Collectively, mGluRs may not directly modulate the processing of spinal nerve ligation-induced neuropathic pain at the spinal level. However, Group III mGluR agonists in the spinal cord may indirectly contribute to the potentiation of morphine antiallodynia, indicating that these agonists might be used as adjuvants for spinal morphine.
Asunto(s)
Analgésicos/uso terapéutico , Agonistas de Aminoácidos Excitadores/uso terapéutico , Morfina/uso terapéutico , Neuralgia/tratamiento farmacológico , Prolina/análogos & derivados , Receptores de Glutamato Metabotrópico/agonistas , Nervios Espinales/lesiones , Analgésicos/clasificación , Analgésicos/farmacología , Animales , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Agonistas de Aminoácidos Excitadores/clasificación , Agonistas de Aminoácidos Excitadores/farmacología , Ligadura , Masculino , Morfina/farmacología , Neuralgia/patología , Dolor/tratamiento farmacológico , Dolor/patología , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Prolina/farmacología , Prolina/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/fisiología , Nervios Espinales/efectos de los fármacos , Resultado del TratamientoRESUMEN
The manipulation of glutamate neurotransmission could represent a potential strategy for the pharmacotherapy of schizophrenic symptoms. Preclinical studies suggest that two subtypes of metabotropic glutamate (mGlu) receptors such as mGlu2/3 and mGlu5 receptors have the potential to ameliorate deficits in schizophrenia. In our study we evaluated the role of a non-specific mGlu receptor agonist ((1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid; 1S,3R-ACPD), mGlu5 receptor agonist or positive modulators ((RS)-2-Chloro-5-hydroxyphenylglycine;CHPG; [(3-Fluoro-phenyl)methylene]hydrazone-3-fluorobenzaldehyde; DFB; 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; CDPPB) and a mGlu2/3 receptor agonist (2,2,2-Trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyrdinylmethyl)ethanesulfonamide hydrochloride; LY-487379) on performance in a cognitive task (Active Allothetic Place Avoidance) after sub-chronic administration of 5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclo-hepten-5,10-imine; MK-801 . The Active Allothetic Place Avoidance task is suitable for assessing the executive function and attention of animals and was previously validated for testing the effect of anti-psychotics. Application of the mGlu2/3 receptor agonist had no effect on cognitive impairment induced by MK-801. However, the mGlu5 receptor agonists ameliorated cognitive impairment induced by MK-801 without affecting locomotion. In conclusion, the mGlu5 receptor agonists could be effective in the treatment of cognitive deficits in patients with schizophrenia. However, the pro-cognitive effect of the agonist of mGlu2/3 receptors was not demonstrated in the present study.
Asunto(s)
Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/tratamiento farmacológico , Cognición/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Animales , Cognición/fisiología , Trastornos del Conocimiento/metabolismo , Maleato de Dizocilpina/administración & dosificación , Agonistas de Aminoácidos Excitadores/clasificación , Agonistas de Aminoácidos Excitadores/uso terapéutico , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratas , Ratas Long-Evans , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamiento farmacológicoRESUMEN
A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.
Asunto(s)
Aminoácidos/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Piridinas/farmacología , Piridonas/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Sulfonamidas/farmacología , Regulación Alostérica , Aminoácidos/química , Animales , Compuestos Bicíclicos con Puentes/química , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Agonistas de Aminoácidos Excitadores/química , Agonistas de Aminoácidos Excitadores/clasificación , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Piridinas/química , Piridonas/química , Piridonas/clasificación , Piridonas/aislamiento & purificación , Proteínas Recombinantes/efectos de los fármacos , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
Properties of AMPA type glutamate receptors widely presented within mammalian central nervous system are reviewed. AMPA receptors belong to ionotropic subclass of glutamate receptors and participate in fast excitatory glutamatergic transmission in the brain. Molecular structure of AMPA receptors consists of several subunits (GluRA1-GluRA4), which display various sensitivity to receptor ligands. These receptors are named according to their selective agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). AMPA receptor modulators represented by several chemical groups: pyrrolidinones (aniracetam), benzothiodiazinedioxides, benzylpiperidines and biarylpropylsulphonamides. These compounds facilitate AMPA receptor-mediated glutamatergic neurotransmission. AMPA receptor modulators enhance cognitive functions (learning and memory), reveal anxiolytic and antidepressant action, suppress the effects of psychostimulant agents, potentiate the effects of antipsychotic drugs, display neuroprotective properties. Positive modulation of AMPA receptor-associated ionic channels was shown to underline the mode of action of these substances that results in enhancement of long-term potentiation (LTP) and increasing neurotrophic factors expression. Preliminary clinical results have shown positive therapeutic effect of these substances in patients with cognitive impairment.
Asunto(s)
Agonistas de Aminoácidos Excitadores/metabolismo , Receptores AMPA/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/metabolismo , Agonistas de Aminoácidos Excitadores/clasificación , Humanos , Canales Iónicos/metabolismo , Receptores AMPA/químicaRESUMEN
The perirhinal cortex is crucially involved in various forms of learning and memory. Decrements in neuronal responsiveness occur in the perirhinal cortex with stimulus repetition during visual recognition performance. However, very little is known concerning the underlying mechanisms of synaptic transmission and plasticity in this cortical region. In this study, we provide evidence demonstrating the presence of functional group I, II and III metabotropic glutamate receptors in the rat perirhinal cortex in vitro. Furthermore, the results demonstrate long-lasting synaptic depression in the perirhinal cortex. Extracellular synaptic responses were recorded from superficial layers of the perirhinal cortex directly below the rhinal sulcus, in response to electrical stimuli delivered in the superficial or intermediate layers to the entorhinal or temporal cortex sides of the rhinal sulcus. Evoked synaptic potentials were depressed during bath perfusion of each of the following: the broad-spectrum metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, the selective group I agonist (R,S)-3,5-dihydroxyphenylglycine, the group II agonist (2S,1'R,2'R,3'R)-(2',3'-dicarboxycyclopropyl)glycine and the group III agonist (S)-2-amino-4-phosphonobutanoate. Furthermore, there was a long-lasting depression of synaptic transmission following washout of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, (R,S)-3,5-dihydroxyphenylglycine or (2S,1'R,2'R,3'R)-(2',3'-dicarboxy-cyclopropyl)glycine. Activation of group III metabotropic glutamate receptors by (S)-2-amino-4-phosphonobutanoate did not result in long-lasting changes in synaptic transmission. Thus, the pharmacological activation of metabotropic glutamate receptors can produce short- or long-term changes in synaptic transmission in the perirhinal cortex. It is possible therefore, that metabotropic glutamate receptors are involved in the decrement in neuronal responsiveness associated with visual recognition in the perirhinal cortex.