RESUMO
Neuropathic pain represents a challenge to clinicians because it is resistant to commonly prescribed analgesics due to its largely unknown mechanisms. Here, we investigated a descending dopaminergic pathway-mediated modulation of trigeminal neuropathic pain. We performed chronic constriction injury of the infraorbital nerve from the maxillary branch of trigeminal nerve to induce trigeminal neuropathic pain in mice. Our retrograde tracing showed that the descending dopaminergic projection from hypothalamic A11 nucleus to spinal trigeminal nucleus caudalis is bilateral. Optogenetic/chemogenetic manipulation of dopamine receptors D1 and D2 in the spinal trigeminal nucleus caudalis produced opposite effects on the nerve injury-induced trigeminal neuropathic pain. Specific excitation of dopaminergic neurons in the A11 nucleus attenuated the trigeminal neuropathic pain through the activation of D2 receptors in the spinal trigeminal nucleus caudalis. Conversely, specific ablation of the A11 dopaminergic neurons exacerbated such pain. Our results suggest that the descending A11-spinal trigeminal nucleus caudalis dopaminergic projection is critical for the modulation of trigeminal neuropathic pain and could be manipulated to treat such pain.
Assuntos
Encéfalo/patologia , Antagonistas de Dopamina/uso terapêutico , Neurônios Dopaminérgicos/patologia , Receptores de Dopamina D2/metabolismo , Espiperona/uso terapêutico , Doenças do Nervo Trigêmeo/terapia , Animais , Benzazepinas/uso terapêutico , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Condicionamento Operante/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Lateralidade Funcional , Hiperalgesia/fisiopatologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Limiar da Dor/fisiologia , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Doenças do Nervo Trigêmeo/fisiopatologiaRESUMO
The possibility of boosting antifibrotic activity of testicular hyaluronidase immobilized on polyethylene oxide with spiperone was studied on the bleomycin models of a single (partially reversible pneumofibrosis) and repeated (irreversible pneumofibrosis) injuries to the alveolar epithelium in C57Bl/6 mice. The antifibrotic effect was more pronounced after successive treatment with immobilized hyaluronidase and spiperone than after individual treatment with each of the compounds: no collagen deposition in the parenchyma of bleomycin-damaged lungs was found. The decrease in inflammatory cell (lymphocytes, macrophages, neutrophils, plasma cells) infiltration of the alveoli and alveolar tracts interstitium in mice treated by immobilized hyaluronidase and spiperone did not differ from the anti-inflammatory effect of spiperone monotherapy.