RESUMO
Neurotropin (NTP)(®), a non-protein extract isolated from the inflamed skin of rabbits inoculated with vaccinia virus, is used clinically for the treatment of neuropathic pain. Moreover, NTP may activate the descending pain inhibitory system. Depression-like behavior is often complicated by chronic pain. However, little is known about NTP-mediated prevention of mood disorders in chronic pain and its molecular mechanisms. We aimed to investigate the effects of NTP on brain-derived neurotrophic factor (BDNF)-mediated signaling and gene expression in chronic pain. In addition, these effects of NTP were compared with pregabalin which is an anticonvulsant, anxiolytic analgesic used to treat neuropathic pain and fibromyalgia. A chronic constriction injury model was established in Sprague-Dawley rats. The pain response was assessed using a paw withdrawal latency (PWL) test and depression was assessed by the immobility time in a forced swim test (FST). NTP was orally administered in two doses of 50 NU (Neurotropin Unit) and 100 NU/kg for 7 days from day 7 after injury. To measure the analgesic and anti-depressant effects of NTP, either K252a (a tyrosine kinase inhibitor), or 5,7-dihydroxy tryptamine (5,7-DHT, a selective toxin for 5-HTergic neurons) was administered by intracerebroventricular injection. Changes in pERK1/2 and pCREB (immunohistochemistry), 5-HT, and BDNF protein level (ELISA) and BDNF mRNA (RT-PCR) were measured in the anterior cingulate cortex (ACC) and in the rostral ventromedial medulla (RVM) 14 days after injury. After injury, the rats showed a decrease in PWL associated with the increase in time of immobility in FST. In this injury model, NTP blocked both the decrease in PWL and the increase in the FST, while pregabalin (10 mg/kg, po.) did not affect the increase in the FST. These effects of NTP were reversed by K252a, and 5,7-DHT. The analgesic effects of pregabalin were not reversed by K252a. NTP normalized the injury-induced excessive activation of pERK1/2 associated with decreased pCREB and BDNF mRNA in the ACC and in the RVM, and these changes were reversed by 5,7-DHT. In contrast, pregabalin did not affect either pCREB or BDNF levels in the chronic pain model. NTP ameliorated chronic pain and pain-related depression by normalizing the induction of BDNF associated with the 5-HTergic system. Pregabalin showed the analgesic effects but had no effects on either depression or the BDNF pathway. These results suggest that NTP may represent an additional drug strategy for chronic pain associated with depression.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dor Crônica/tratamento farmacológico , Polissacarídeos/uso terapêutico , Analgésicos/farmacologia , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/genética , Dor Crônica/genética , Dor Crônica/patologia , Constrição Patológica , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Polissacarídeos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Coelhos , Ratos Sprague-Dawley , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/metabolismo , NataçãoRESUMO
Depression-like behavior is often complicated by chronic pain. Antidepressants including imipramine (IMI) are widely used to treat chronic pain, but the mechanisms are not fully understood. Brain-derived neurotrophic factor (BDNF) is a neuromodulator that reduces depression by regulating synaptic transmission. We aimed to characterize the antidepressant effects of IMI without analgesia based on BDNF (trkB)-mediated signaling and gene expression in chronic pain. A chronic constriction injury (CCI) model was constructed in Sprague-Dawley (SD) rats. IMI (5 mg/kg, i.p.) was administered from day 10 after CCI. The pain response was assessed using the paw withdrawal latency (PWL) and depression was judged from the immobility time in a forced swim test. Anti-BDNF antibody, K252a, or 5,7-dihydroxytryptamine (5,7-DHT) were used to examine the antidepressant effects of imipramine. Changes in pERK1/2 (immunohistochemistry), 5-HT and BDNF (ELISA), and BDNF mRNA (RT-PCR) were measured in the anterior cingulate cortex (ACC), rostral ventromedial medulla (RVM), and spinal cord. After CCI, rats showed decreased PWL and increased immobility time. A low dose of IMI reduced the immobility time without having analgesic effects. This antidepressant effect was reversed by anti-BDNF antibody, K252a, and 5,7-DHT. IMI reduced excessive activation of pERK1/2 associated with decreased pCREB and BDNF mRNA, and these changes were reversed by 5,7-DHT. These results show that IMI reduces pain-related negative emotion without influencing pain and that this effect is diminished by denervation of 5-HT neurons and by anti-BDNF treatment. IMI also normalizes derangement of ERK/CREB coupling, which leads to induction of BDNF. This suggests a possible interaction between 5-HT and BDNF.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Dor Crônica/tratamento farmacológico , Dor Crônica/genética , Emoções , Imipramina/uso terapêutico , 5,7-Di-Hidroxitriptamina/farmacologia , 5,7-Di-Hidroxitriptamina/uso terapêutico , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dor Crônica/fisiopatologia , Constrição Patológica , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Emoções/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Giro do Cíngulo/patologia , Imipramina/farmacologia , Masculino , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Serotonina/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologiaRESUMO
Chronic pain with mood disorder, resulting from a peripheral nerve injury, is a serious clinical problem affecting the quality of life. A lack of brain-derived neurotrophic factor (BDNF) and abnormal intercellular signaling in the brain can mediate this symptom. BDNF is induced in cultured neurons by 4-methylcatechol (4-MC), but little is known about its role in pain-emotion. Thus, we characterized the actions of 4-MC on TrkB receptor-related pERK and BDNF mRNA in discreet brain regions related to pain-emotion after chronic pain in rat. Rats implanted with a stainless steel cannula into the lateral ventricular were subjected to chronic constriction injury (CCI). Pain was assessed by changes in paw withdrawal latency (PWL) to heat stimuli after CCI. Immobility time during the forced swimming testing was measured for depression-like behavior. Analgesic and antidepression modulations with 4-MC were examined by an anti-BDNF antibody (K252a, a TrkB receptor inhibitor). The animals were perfused and fixed (4% paraformaldehyde) for immunohistochemistry analysis (c-FOS/pERK). BDNF mRNA expression (anterior cingulate cortex) was determined using reverse transcription-PCR. Rats showed a sustained decrease in PWL, associated with a prolonged immobility time after CCI. 4-MC reduced decreases in PWL and increased immobility time. 4-MC reduced increases in pERK immunoreactivity and decreases in BDNF mRNA expression in regions related to pain and the limbic system. Anti-BDNF blocked effects induced by 4-MC. We suggest that a lack of BDNF associated with activated extracellular signal-regulated kinase in the pain-emotion network may be involved in depression-like behavior during chronic pain. 4-MC ameliorates pain-emotion symptoms by inducing BDNF and normalizing pERK activities.
