Neuropathic pain is a debilitating clinical problem and difficult to treat. Nerve injury causes a long-lasting reduction in K+ channel expression in the dorsal root ganglion (DRG), but little is known about the epigenetic mechanisms involved. Here we show that nerve injury increased H3K9me2 occupancy at Kcna4, Kcnd2, Kcnq2 and Kcnma1 promoters but did not affect DNA methylation levels of these genes in DRGs. Nerve injury increased activity of G9a, histone deacetylases and EZH2, but only G9a inhibition consistently restored K+ channel expression. Selective G9a knockout in DRG neurons completely blocked K+ channel silencing and chronic pain development after nerve injury. Remarkably, RNA sequencing analysis revealed that G9a inhibition not only reactivated 40 of 42 silenced K+ channel genes but also normalized 638 genes down- or up-regulated by nerve injury. Thus G9a plays a dominant role in transcriptional repression of K+ channels and in acute-to-chronic pain transition after nerve injury.
Paraventricular nucleus (PVN) neurons that project to the spinal cord are important in the control of sympathetic outflow. Angiotensin II (Ang II) can stimulate PVN neurons, but its cellular mechanisms are not clear. In this study, we determined the effect of Ang II on the excitatory and inhibitory synaptic inputs to spinally projecting PVN neurons. Whole-cell patch-clamp recordings were performed on PVN neurons labeled by a retrograde fluorescence tracer injected into the thoracic spinal cord of rats. Immunocytochemistry labeling revealed that the immunoreactivity of angiotensin type 1 (AT1) receptors was colocalized with a presynaptic marker, synaptophysin, in the PVN. Application of 0.1-5 microm Ang II significantly decreased the amplitude of evoked GABAergic IPSCs in a concentration-dependent manner. Also, Ang II decreased the frequency of miniature IPSCs from 2.56 +/- 0.45 to 1.05 +/- 0.20 Hz (p < 0.05; n = 12), without affecting the amplitude and the decay time constant. The effect of Ang II on miniature IPSCs was blocked by losartan but not PD123319. However, Ang II had no effect on the evoked glutamatergic EPSCs and did not alter the frequency and amplitude of miniature EPSCs at concentrations that attenuated IPSCs. Furthermore, Ang II increased the firing rate of PVN neurons from 3.75 +/- 0.36 to 7.89 +/- 0.85 Hz (p < 0.05; n = 9), and such an effect was abolished by losartan. In addition, Ang II failed to excite PVN neurons in the presence of bicuculline. Thus, this study provides substantial new evidence that Ang II excites spinally projecting PVN neurons by attenuation of GABAergic synaptic inputs through activation of presynaptic AT1 receptors.
Myocardial ischaemia causes the release of metabolites such as bradykinin, which stimulates cardiac sensory receptors to evoke a sympathoexcitatory reflex. However, the molecular identity of the afferent neurons and fibres mediating this reflex response is not clear. In this study, we tested the hypothesis that the cardiogenic sympathoexcitatory reflex is mediated by capsaicin‐sensitive afferent fibres. Enhanced immunofluorescence labelling revealed that vanilloid receptor 1 (VR1)‐containing afferent nerve fibres were present on the epicardial surface of the rat heart. Resiniferatoxin (RTX), a potent analogue of capsaicin, was used to deplete capsaicin‐sensitive afferent fibres in rats. Depletion of these fibres was confirmed by a substantial reduction of VR1 immunoreactivity in the epicardium and dorsal root ganglia. The thermal sensitivity was also diminished in RTX‐treated rats. Renal sympathetic nerve activity (RSNA) and blood pressure were recorded in anaesthetized rats during epicardial application of bradykinin or capsaicin. In vehicle‐treated rats, epicardial bradykinin (10 μg ml−1) or capsaicin (10 μg ml−1) application produced a significant increase in RSNA and arterial blood pressure. The RSNA and blood pressure responses caused by bradykinin and capsaicin were completely abolished in RTX‐treated rats. Furthermore, epicardial application of iodo‐RTX, a highly specific antagonist of VR1 receptors, blocked capsaicin‐ but not bradykinin‐induced sympathoexcitatory responses. Thus, these data provide important histological and functional evidence that the heart is innervated by VR1‐expressing afferent nerves and these afferent nerves are essential for the cardiogenic sympathoexcitatory reflex during myocardial ischaemia.
Abstract-The paraventricular nucleus (PVN) of the hypothalamus is critical to the regulation of sympathetic output. The PVN hyperactivity is known to cause increased sympathetic nerve activity in spontaneously hypertensive rats (SHRs). The purpose of this study was to determine whether glutamatergic input to the PVN contributes to heightened sympathetic outflow in hypertension. Lumbar sympathetic nerve activity, mean arterial blood pressure, and heart rate were recorded from anesthetized SHRs and Wistar-Kyoto (WKY) rats. Bilateral microinjection of an N-methyl-Daspartate receptor antagonist, 2-amino-5-phosphonopentanoic acid, or a non-N-methyl-D-aspartate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, into the PVN dose-dependently decreased lumbar sympathetic nerve activity, mean arterial blood pressure, and heart rate in SHRs but not in WKY rats. Bilateral microinjection of kynurenic acid into the PVN also significantly decreased lumbar sympathetic nerve activity, mean arterial blood pressure, and heart rate in SHRs but not in WKY rats. Furthermore, microinjection of gabazine, a specific GABA A receptor antagonist, into the PVN increased lumbar sympathetic nerve activity, mean arterial blood pressure, and heart rate in both SHRs and WKY rats. Notably, this response was significantly attenuated in SHRs compared with that in WKY rats. In addition, kynurenic acid abolished the sympathoexcitatory and pressor responses to microinjection of gabazine into the PVN in both SHRs and WKY rats. Thus, this study provides new functional evidence that resting sympathetic vasomotor tone is maintained by tonic glutamatergic input in the PVN in SHRs. Removal of GABAergic inhibition results in augmented glutamatergic input in the PVN, which probably constitutes an important source of excitatory drive to the brain stem vasomotor neurons in hypertension. Key Words: excitatory amino acids Ⅲ hypothalamus Ⅲ sympathetic nervous system Ⅲ synaptic transmission Ⅲ autonomic nervous system Ⅲ NMDA receptors H ypertension is a significant risk factor for cardiovascular, renal, and cerebrovascular disorders. Increased sympathetic activity is often associated with hypertension and may contribute to the pathogenesis and maintenance of hypertension. 1,2 Previous studies suggested that altered central mechanisms are responsible for the elevated sympathetic outflow and arterial blood pressure in hypertension. In this regard, transection of the brain caudal to the hypothalamus reduces arterial blood pressure in spontaneously hypertensive rats (SHRs) but not in Wistar-Kyoto (WKY) rats. 3 The paraventricular nucleus (PVN) of the hypothalamus is an important region for the regulation of sympathetic output and arterial blood pressure. 4 -7 Lesions of the PVN in hypertensive rats, such as SHRs, Dahl salt-sensitive rats, and rats with renal hypertension, decrease blood pressure. 8 -11 Furthermore, inhibition of the PVN with muscimol reduces the blood pressure and sympathetic nerve activity in SHRs. 12 Thus, hyperactivity of PVN neurons may d...
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