RESUMO
Patients with chronic pain often have accompanying cognitive deficiency, which may reduce their quality of life and hamper efficient medical treatment. Alteration of extracellular glycine concentration may affect cognitive function and spinal pain signaling. In the present study, we assessed recognition memory by novel-object recognition and found that mice developing mechanical hypersensitivity after peripheral nerve injury exhibited impaired recognition ability for novelty, which was never observed in mice provided the selective glycine transporter 1 (GlyT1) inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS) systemically. Although systemic NFPS generated analgesia via inhibitory effects of glycine in the spinal cord, the cognitive impairment in neuropathic mice was not restored upon relief of pain alone by intrathecal injection of NFPS. Whole-cell recordings were then made from hippocampal CA1 pyramidal neurons, and the effect of exogenously applied glycine or its endogenous increase by blockade of GlyT1 with NFPS on N-methyl-D-aspartate receptor-mediated excitatory postsynaptic currents (NMDA-EPSCs) was investigated in slices prepared from neuropathic mice and mice subjected to sham treatment. In slices from neuropathic mice, NMDA-EPSCs were less potentiated by glycine, whereas they were augmented by NFPS even at lower concentrations. After treating the slices with either NFPS or the glial-selective metabolic blocker fluoroacetate, glycine potentiated NMDA-EPSCs equally in slices from neuropathic and sham-treated mice. These findings imply that chronic pain has a crucial influence on hippocampal plasticity related to cognitive function, and strongly suggest that increasing the extracellular level of glycine via blockade of GlyT1 is a potential therapeutic approach for chronic pain with memory impairment. Chronic pain crucially influences hippocampal plasticity related to cognitive function. Increasing the extracellular level of glycine via blockade of GlyT1 is a potential therapeutic approach for chronic pain with memory impairment.
Assuntos
Transtornos Cognitivos/etiologia , Glicina/metabolismo , Hipocampo/metabolismo , Neuropatia Ciática/complicações , Neuropatia Ciática/patologia , Animais , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Fluoracetatos/farmacologia , Glicina/farmacologia , Interações Ervas-Drogas , Hipocampo/patologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Medição da Dor , Limiar da Dor/fisiologia , Técnicas de Patch-Clamp , Reconhecimento Psicológico , Sarcosina/análogos & derivados , Sarcosina/uso terapêutico , Neuropatia Ciática/tratamento farmacológicoRESUMO
The antiepileptic drugs gabapentin and pregabalin exhibit well-established analgesic effects in patients with several neuropathic conditions. In the present study, we examined their effects on mechanical hypersensitivity in mice subjected to weight-drop spinal cord injury. Hindlimb motor function and mechanical hypersensitivity were evaluated using the Basso-Beattie-Bresnahan (BBB) locomotor rating scale and the von Frey test, respectively, for 4 weeks after spinal cord injury. Despite gradual recovery of hindlimb motor function after spinal cord injury, mice exhibited continuous development of mechanical hypersensitivity. Gabapentin (30 and 100 mg/kg) and pregabalin (10 and 30 mg/kg), administered intraperitoneally on the 28th day after spinal cord injury, reduced mechanical hypersensitivity in a dose-dependent manner. These results suggest that gabapentin and pregabalin could be useful therapeutic tools for patients with neuropathic pain after spinal cord injury.