RESUMEN
The hippocampus is an important region for the interaction between depression and pain. Studies show that the P2X4 receptor plays key role in neuropathic pain. This work investigated the potential implication of the P2X4 receptor in the hippocampus in comorbidity of chronic pain and depression. The rat model induced by chronic constriction injury (CCI) plus unpredictable chronic mild stress (UCMS) was used in this study. Our data showed that CCI plus UCMS treatment resulted in abnormal changes in pain and depressive-like behaviors in the rat, accompanied by the upregulated expression of P2X4, NLRP3 (NOD-like receptor protein 3) inflammasome, and interleukin-1ß and the activation of p38 MAPK in the hippocampus. The P2X4 antagonist 5-BDBD reversed these abnormal changes in the hippocampus, relieved hippocampal neuronal damage, and alleviated the abnormal pain and depressive-like behaviors in the CCI plus UCMS treated rats. These findings suggest that the P2X4 receptor in the hippocampus may mediate and significantly contribute to the pathological processes of comorbid pain and depression.
Asunto(s)
Dolor Crónico , Receptores Purinérgicos P2X4 , Animales , Comorbilidad , Depresión , Hipocampo , RatasRESUMEN
Glucokinase (GCK) may be involved in inflammatory pathological changes, while the P2X3 receptor in the stellate ganglia (SG) is related to diabetic cardiac autonomic neuropathy. In this study, we explored the relationship between the upregulated GCK in SG and diabetic cardiac sympathy. The expression and location of GCK and P2X3 in SG of type 2 diabetes mellitus (T2DM) rats were assessed. Changes in cardiac function were determined by measuring blood pressure, sympathetic nerve activity, heart rate, and heart rate variability. P2X3 agonist-activated currents in isolated stellate ganglion neurons and cultured human embryonic kidney 293 (HEK293) cells were recorded using whole-cell patch clamp techniques. The upregulated expression of GCK in SG of T2DM rats was decreased after treatment with GCK short hairpin RNA (shRNA). GCK shRNA treatment also improved the blood pressure, sympathetic nerve activity, heart rate, and heart rate variability in T2DM rats. By contrast, the expression of P2X3 and tumor necrosis factor α (TNF-α) was lessened by GCK shRNA treatment. In addition, adenosine triphosphate (ATP)-activated currents in stellate ganglion neurons and HEK293 cells co-transfected with GCK and P2X3 receptor plasmids were reduced after GCK shRNA treatment. In T2DM rats, knockdown of GCK relieved the diabetic cardiac sympathy mediated by P2X3 receptor-involved upregulation of GCK in SG.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Neuropatías Diabéticas/metabolismo , Glucoquinasa/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Ganglio Estrellado/metabolismo , Animales , Presión Sanguínea/fisiología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Neuropatías Diabéticas/fisiopatología , Células HEK293 , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Ganglio Estrellado/fisiopatología , Sistema Nervioso Simpático/metabolismo , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
The celiac ganglion projects its postganglionic (including purinergic) fibers to the liver. P2Y12 receptor is one of the P2Y family members. We found that the expression levels of P2Y12 receptor in both celiac ganglia and liver were increased in type 2 diabetes mellitus (T2DM) rats which also displayed an enhanced activity of celiac sympathetic nerve discharge (SND). In addition, a marked decrease of hepatic glucokinase (GK) expression was accompanied by reduced hepatic glycogen synthesis in T2DM rats, whereas meanwhile the levels of NLRP3, active caspase-1, NF-κB, and interleukin-1ß were elevated. All these abnormal alterations could be largely reversed after treatment of short hairpin RNA (shRNA) targeting P2Y12. Our results indicate that the silence of P2Y12 by shRNA may effectively correct the anomalous activity of celiac SND and improve the dysfunctional hepatic glucokinase by counteracting hepatocyte inflammation and likely pyroptosis due to activated NLRP3 inflammasome and caspase-1 signaling, thereby attenuating hyperglycemia in T2DM rats.