541 results on '"Chen, Shao-Rui"'
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202. Spinal Endogenous Acetylcholine Contributes to the Analgesic Effect of Systemic Morphine in Rats
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Chen, Shao-Rui, primary and Pan, Hui-Lin, additional
- Published
- 2001
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203. G9a is essential for epigenetic silencing of K+channel genes in acute-to-chronic pain transition
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Laumet, Geoffroy, Garriga, Judit, Chen, Shao-Rui, Zhang, Yuhao, Li, De-Pei, Smith, Trevor M, Dong, Yingchun, Jelinek, Jaroslav, Cesaroni, Matteo, Issa, Jean-Pierre, and Pan, Hui-Lin
- Abstract
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. We found that nerve injury increased dimethylation of Lys9 on histone H3 (H3K9me2) at Kcna4, Kcnd2, Kcnq2 and Kcnma1 promoters but did not affect levels of DNA methylation on these genes in DRGs. Nerve injury increased activity of euchromatic histone-lysine N-methyltransferase-2 (G9a), histone deacetylases and enhancer of zeste homolog-2 (EZH2), but only G9a inhibition consistently restored K+channel expression. Selective knockout of the gene encoding G9a 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 genes associated with K+channels but also normalized 638 genes down- or upregulated by nerve injury. Thus G9a has a dominant function in transcriptional repression of K+channels and in acute-to-chronic pain transition after nerve injury.
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- 2015
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204. Role of spinal muscarinic and nicotinic receptors in clonidine-induced nitric oxide release in a rat model of neuropathic pain
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Xu, Zemin, primary, Chen, Shao-Rui, additional, C. Eisenach, James, additional, and Pan, Hui-Lin, additional
- Published
- 2000
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205. Synergistic Effect between Intrathecal Non-NMDA Antagonist and Gabapentin on Allodynia Induced by Spinal Nerve Ligation in Rats
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Chen, Shao-Rui, primary, Eisenach, James C., additional, McCaslin, Patrick P., additional, and Pan, Hui-Lin, additional
- Published
- 2000
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206. Protein kinase CK2 contributes to diminished small conductance Ca2+-activated K+ channel activity of hypothalamic pre-sympathetic neurons in hypertension.
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Pachuau, Judith, Li, De‐Pei, Chen, Shao‐Rui, Lee, Hae‐Ahm, and Pan, Hui‐Lin
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PROTEIN kinase CK2 ,PROTEIN kinase regulation ,NEURAL physiology ,PHOSPHOTRANSFERASES ,HYPERTENSION ,THERAPEUTICS - Abstract
Small conductance calcium-activated K
+ ( SK) channels regulate neuronal excitability. However, little is known about changes in SK channel activity of pre-sympathetic neurons in the hypothalamic paraventricular nucleus ( PVN) in essential hypertension. SK channels, calmodulin, and casein kinase II ( CK2) form a molecular complex. Because CK2 is up-regulated in the PVN in spontaneously hypertensive rats ( SHRs), we hypothesized that CK2 increases calmodulin phosphorylation and contributes to diminished SK channel activity in PVN pre-sympathetic neurons in SHRs. Perforated whole-cell recordings were performed on retrogradely labeled spinally projecting PVN neurons in Wistar-Kyoto ( WKY) rats and SHRs. Blocking SK channels with apamin significantly increased the firing rate of PVN neurons in WKY rats but not in SHRs. CK2 inhibition restored the stimulatory effect of apamin on the firing activity of PVN neurons in SHRs. Furthermore, apamin-sensitive SK currents and depolarization-induced medium after-hyperpolarization potentials of PVN neurons were significantly larger in WKY rats than in SHRs. CK2 inhibition significantly increased the SK channel current and medium after-depolarization potential of PVN neurons in SHRs. In addition, CK2-mediated calmodulin phosphorylation level in the PVN was significantly higher in SHRs than in WKY rats. Although SK3 was detected in the PVN, its expression level did not differ significantly between SHRs and WKY rats. Our findings suggest that CK2-mediated calmodulin phosphorylation is increased and contributes to diminished SK channel function of PVN pre-sympathetic neurons in SHRs. This information advances our understanding of the mechanisms underlying hyperactivity of PVN pre-sympathetic neurons and increased sympathetic vasomotor tone in hypertension. [ABSTRACT FROM AUTHOR]- Published
- 2014
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207. Nitric oxide stimulates glutamatergic synaptic inputs to baroreceptor neurons through potentiation of Cav2.2-mediated Ca2+ currents.
- Author
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Li, De-Pei and Chen, Shao-Rui
- Subjects
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NITRIC-oxide synthases , *EXCITATORY amino acid agents , *BARORECEPTORS , *NEURONS , *CEREBROSPINAL fluid , *EXCITATORY postsynaptic potential - Abstract
Highlights: [•] Nitric oxide increases presynaptic glutamate release to baroreceptor NTS neurons. [•] Nitric oxide increases N-type Ca2+ currents in baroreceptor NTS neurons in nodose ganglion. [•] Cav2.2 subunit is present on the baroreceptor afferent nerve terminals. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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208. Role of protons in activation of cardiac sympathetic C‐fibre afferents during ischaemia in cats
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Pan, Hui‐Lin, primary, Longhurst, John C., additional, Eisenach, James C., additional, and Chen, Shao‐Rui, additional
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- 1999
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209. Intrathecal Clonidine Alleviates Allodynia in Neuropathic Rats
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Pan, Hui-Lin, primary, Chen, Shao-Rui, additional, and Eisenach, James C., additional
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- 1999
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210. Role of Spinal NO in Antiallodynic Effect of Intrathecal Clonidine in Neuropathic Rats
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Pan, Hui-Lin, primary, Chen, Shao-Rui, additional, and Eisenach, James C., additional
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- 1998
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211. Role of spinal NO in the antiallodynic effect of intrathecal clonidine in neuropathic rats
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Pan, Hui-Lin, primary, Chen, Shao-Rui, additional, and Eisenach, James C., additional
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- 1998
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212. Intrathecal clonidine alleviates allodynia in neuropathic rats
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Pan, Hui-Lin, primary, Xu, Zemin, additional, Chen, Shao-Rui, additional, and Eisenach, James C., additional
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- 1998
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213. Diabetic neuropathy enhances voltage-activated Ca2+ channel activity and its control by M4 muscarinic receptors in primary sensory neurons.
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Cao, Xue-Hong, Byun, Hee Sun, Chen, Shao-Rui, and Pan, Hui-Lin
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DIABETIC neuropathies ,MUSCARINIC receptors ,ANIMAL models of diabetes ,LABORATORY rats ,SENSORY neurons ,MESSENGER RNA ,CHOLINERGIC receptors ,ANALGESIA - Abstract
J. Neurochem. (2011) 119, 594-603. Abstract Painful neuropathy is one of the most serious complications of diabetes and remains difficult to treat. The muscarinic acetylcholine receptor (mAChR) agonists have a profound analgesic effect on painful diabetic neuropathy. Here we determined changes in T-type and high voltage-activated Ca
2+ channels (HVACCs) and their regulation by mAChRs in dorsal root ganglion (DRG) neurons in a rat model of diabetic neuropathy. The HVACC currents in large neurons, T-type currents in medium and large neurons, the percentage of small DRG neurons with T-type currents, and the Cav3.2 mRNA level were significantly increased in diabetic rats compared with those in control rats. The mAChR agonist oxotremorine-M significantly inhibited HVACCs in a greater proportion of DRG neurons with and without T-type currents in diabetic than in control rats. In contrast, oxotremorine-M had no effect on HVACCs in small and large neurons with T-type currents and in most medium neurons with T-type currents from control rats. The M2 and M4 antagonist himbacine abolished the effect of oxotremorine-M on HVACCs in both groups. The selective M4 antagonist muscarinic toxin-3 caused a greater attenuation of the effect of oxotremorine-M on HVACCs in small and medium DRG neurons in diabetic than in control rats. Additionally, the mRNA and protein levels of M4 , but not M2 , in the DRG were significantly greater in diabetic than in control rats. Our findings suggest that diabetic neuropathy potentiates the activity of T-type and HVACCs in primary sensory neurons. M4 mAChRs are up-regulated in DRG neurons and probably account for increased muscarinic analgesic effects in diabetic neuropathic pain. [ABSTRACT FROM AUTHOR]- Published
- 2011
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214. Potentiation of spinal α2-adrenoceptor analgesia in rats deficient in TRPV1-expressing afferent neurons
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Chen, Shao-Rui, Pan, Hao-Min, Richardson, Timothy E., and Pan, Hui-Lin
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ADRENERGIC receptors , *SENSORY neurons , *ANALGESIA , *PROTEIN kinase C - Abstract
Abstract: The α2-adrenoceptors (α2-ARs) are located on primary afferent terminals and on neurons in the spinal cord dorsal horn. However, their relative contribution to the analgesic effect of the α2-AR agonists is not known. In this study, we determined the role of certain presynaptic α2-ARs in the antinociceptive effect produced by intrathecal administration of the α2-AR agonist clonidine. TRPV1-expressing sensory neurons were removed by resiniferatoxin (RTX). The effect of intrathecal injection of clonidine was measured by testing the paw withdrawal response to noxious mechanical or heat stimuli. In RTX-treated rats, the α2A-AR-immunoreactivity co-expressed with TRPV1-expressing terminals in the spinal cord was eliminated. However, the α2C-AR-immunoreactivity in the spinal cord was little changed. Surprisingly, intrathecal administration of clonidine produced a much greater increase in the mechanical withdrawal threshold in RTX- than in vehicle-treated rats. The duration of the clonidine effect was also significantly increased in RTX-treated rats. Furthermore, in the vehicle-treated group, although intrathecal injection of clonidine produced a large increase in the thermal withdrawal latency, it only had a small and short-lasting effect on the mechanical withdrawal threshold. This study provides new information that the antinociceptive effect of spinally administered α2-AR agonists is largely modality-specific. Loss of TRPV1-expressing sensory neurons leads to a reduction in presynaptic α2A-ARs but paradoxically potentiates the effect of clonidine on mechano-nociception. [Copyright &y& Elsevier]
- Published
- 2007
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215. Altered synaptic input and GABAB receptor function in spinal superficial dorsal horn neurons in rats with diabetic neuropathy.
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Wang, Xiu-Li, Zhang, Hong-Mei, Chen, Shao-Rui, and Pan, Hui-Lin
- Abstract
Hyperactivity of spinal dorsal horn neurons plays an important role in the development of diabetic neuropathic pain. However, little is known as to whether synaptic input to spinal dorsal horn neurons is altered in diabetic neuropathy. Also, the function of GABA
B receptors in the control of synaptic input to dorsal horn neurons in diabetes remains poorly understood. To determine the changes in synaptic input to dorsal horn neurons and the GABAB receptor function in streptozotocin-induced diabetes, we performed whole-cell recording (GDP-β-S included in the internal solution) on lamina II neurons in rat spinal cord slices. The frequency of glutamatergic mEPSCs and the amplitude of monosynaptic EPSCs evoked from the dorsal root were significantly higher in diabetic than in control rats. On the other hand, the basal frequency and amplitude of GABAergic spontaneous IPSCs and mIPSCs and those of glycinergic spontaneous IPSCs and mIPSCs did not differ significantly between control and diabetic rats. The GABAB agonist baclofen produced a significantly greater reduction in dorsal root-evoked EPSCs and the frequency of mEPSCs in control than in diabetic rats. However, the inhibitory effect of baclofen on GABAergic and glycinergic spontaneous IPSCs and mIPSCs was not significantly different in the two groups. These findings suggest that increased glutamatergic input from primary afferents to dorsal horn neurons may contribute to synaptic plasticity and central sensitization in diabetic neuropathic pain. Furthermore, the function of presynaptic GABAB receptors at primary afferent terminals, but not that on GABAergic and glycinergic interneurons, in the spinal cord is reduced in diabetic neuropathy. [ABSTRACT FROM AUTHOR]- Published
- 2007
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216. Regulation of synaptic inputs to paraventricular-spinal output neurons by alpha2 adrenergic receptors.
- Author
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Li De-Pei, Atnip Lindsay M, Chen Shao-Rui, and Pan Hui-Lin
- Subjects
NEURONS ,ADRENERGIC receptors ,CENTRAL nervous system ,BRAIN stem ,GABA - Abstract
Neurons in the paraventricular nucleus (PVN) that project to the brain stem and spinal cord are important for autonomic regulation. The excitability of preautonomic PVN neurons is controlled by the noradrenergic input from the brain stem. In this study, we determined the role of alpha(2) adrenergic receptors in the regulation of excitatory and inhibitory synaptic inputs to spinally projecting PVN neurons. Excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) were recorded using whole cell voltage-clamp techniques on PVN neurons labeled by a retrograde fluorescence tracer injected into the thoracic spinal cord of rats. Bath application of 5-20 muM clonidine, an alpha(2) receptor agonist, significantly reduced the amplitude of evoked GABAergic IPSCs in a dose-dependent manner. Also, 10 microM clonidine significantly decreased the frequency (from 2.68 +/- 0.41 to 1.22 +/- 0.40 Hz) but not the amplitude of miniature IPSCs (mIPSCs), and this effect was blocked by the alpha(2) receptor antagonist yohimbine. Furthermore, clonidine increased the paired-pulse ratio of evoked IPSCs from 1.25 +/- 0.05 to 1.61 +/- 0.08 (P < 0.05). On the other hand, clonidine had little effect on evoked glutamatergic EPSCs, mEPSCs, and the paired-pulse ratio of evoked EPSCs in most labeled cells examined. Additionally, immunofluorescence labeling revealed that the alpha(2A) receptor and GABA immunoreactivities were co-localized in close apposition to labeled PVN neurons. Collectively, these data suggest that stimulation of alpha(2) adrenergic receptors primarily attenuates GABAergic inputs to PVN output neurons to the spinal cord. The presynaptic alpha(2) receptors function as heteroreceptors to modulate synaptic GABA release and contribute to the hypothalamic regulation of sympathetic outflow. [ABSTRACT FROM AUTHOR]
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- 2005
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217. Antinociceptive effect of morphine, but not mu opioid receptor number, is attenuated in the spinal cord of diabetic rats.
- Author
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Chen, Shao-Rui and Pan, Hui-Lin
- Published
- 2003
218. Spinal GABAB receptors mediate antinociceptive actions of cholinergic agents in normal and diabetic rats
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Chen, Shao-Rui and Pan, Hui-Lin
- Subjects
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MUSCARINIC receptors , *ACETYLCHOLINESTERASE , *BRAIN research - Abstract
Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors can produce antinociception. However, the mechanisms of the action of cholinergic agents in the spinal cord are not fully understood. Activation of spinal muscarinic receptors evokes γ-aminobutyric acid (GABA) release, which reduces the glutamatergic synaptic input to dorsal horn neurons through GABAB receptors. In this study, we determined the functional role of spinal GABAB receptors in the antinociceptive action of intrathecal cholinergic agents in normal rats and in a rat model of diabetic neuropathic pain. Diabetes was induced by intraperitoneal streptozotocin in rats. The intrathecal catheter was inserted with its tip positioned at the lumbar spinal level. Nociceptive threshold was measured by the paw withdrawal latency in response to a radiant heat stimulus in normal rats. Mechanical allodynia in diabetic rats was determined by von Frey filaments applied to the hindpaw. The effect of intrathecal muscarine or neostigmine was examined through pretreatment with the specific GABAB receptor antagonist, CGP55845, or its vehicle. Intrathecal injection of muscarine or neostigmine significantly increased the withdrawal latency in response to a heat stimulus in normal rats and the withdrawal threshold in response to application of von Frey filaments in diabetic rats. Intrathecal pretreatment with CGP55845 significantly attenuated the effect of both muscarine or neostigmine in normal rats. Furthermore, the antiallodynic effect of intrathecal neostigmine and muscarine was largely eliminated by CGP55845 in diabetic rats. These data suggest that the GABAB receptors in the spinal cord mediate both the antinociceptive and antiallodynic actions of intrathecal muscarine or neostigmine in normal rats and in a rat model of diabetic neuropathic pain. This study provides new functional evidence that activation of spinal GABAB receptors is one of the important mechanisms underlying the antinociceptive action of intrathecal cholinergic agents. [Copyright &y& Elsevier]
- Published
- 2003
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219. Functional mu opioid receptors are reduced in the spinal cord dorsal horn of diabetic rats.
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Chen, Shao-Rui, Sweigart, Kristi L, Lakoski, Joan M, and Pan, Hui-Lin
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- 2002
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220. Role of Presynaptic Muscarinic and GABAB Receptors in Spinal Glutamate Release and Cholinergic Analgesia in Rats.
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Li, De-Pei, Chen, Shao-Rui, Pan, Yu-Zhen, Levey, Allan I., and Pan, Hui-Lin
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- 2002
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221. α2δ-1 switches the phenotype of synaptic AMPA receptors by physically disrupting heteromeric subunit assembly.
- Author
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Li, Lingyong, Chen, Shao-Rui, Zhou, Meng-Hua, Wang, Li, Li, De-Pei, Chen, Hong, Lee, Garam, Jayaraman, Vasanthi, and Pan, Hui-Lin
- Abstract
Many neurological disorders show an increased prevalence of GluA2-lacking, Ca
2+ -permeable AMPA receptors (CP-AMPARs), which dramatically alters synaptic function. However, the molecular mechanism underlying this distinct synaptic plasticity remains enigmatic. Here, we show that nerve injury potentiates postsynaptic, but not presynaptic, CP-AMPARs in the spinal dorsal horn via α2δ-1. Overexpressing α2δ-1, previously regarded as a Ca2+ channel subunit, augments CP-AMPAR levels at the cell surface and synapse. Mechanistically, α2δ-1 physically interacts with both GluA1 and GluA2 via its C terminus, inhibits the GluA1/GluA2 heteromeric assembly, and increases GluA2 retention in the endoplasmic reticulum. Consequently, α2δ-1 diminishes the availability and synaptic expression of GluA1/GluA2 heterotetramers in the spinal cord in neuropathic pain. Inhibiting α2δ-1 with gabapentin or disrupting the α2δ-1-AMPAR complex fully restores the intracellular assembly and synaptic dominance of heteromeric GluA1/GluA2 receptors. Thus, α2δ-1 is a pivotal AMPAR-interacting protein that controls the subunit composition and Ca2+ permeability of postsynaptic AMPARs. [Display omitted] • Nerve injury augments postsynaptic Ca2+ -permeable AMPARs in the spinal cord via α2δ-1 • α2δ-1, but not α2δ-2 or α2δ-3, interacts directly with GluA1 and GluA2 via its C terminus • α2δ-1 disrupts heteromeric, but not homomeric, assembly of GluA1 and GluA2 in the ER • Gabapentin restores assembly and synaptic expression of GluA1/GluA2 in neuropathic pain Li et al. show that α2δ-1 directly interacts with GluA1 and GluA2 subunits via its C terminus and disrupts intracellular assembly of GluA1/GluA2 heteromers. Gabapentinoids reduce neuropathic pain by restoring assembly and synaptic prevalence of heteromeric AMPA receptors in the spinal cord. [ABSTRACT FROM AUTHOR]- Published
- 2021
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222. Functional plasticity of group II metabotropic glutamate receptors in regulating spinal excitatory and inhibitory synaptic input in neuropathic pain.
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Zhou, Hong-Yi, Chen, Shao-Rui, Chen, Hong, and Pan, Hui-Lin
- Abstract
Metabotropic glutamate receptors (mGluRs) are involved in the modulation of synaptic transmission and plasticity. Group II mGluRs in the spinal cord regulate glutamatergic input, but their functional changes in neuropathic pain are not clear. In this study, we determined the plasticity of spinal group II mGluRs in controlling excitatory and inhibitory synaptic transmission and nociception in neuropathic pain. Neuropathic pain was induced by spinal nerve ligation in rats, and whole-cell voltage-clamp recordings of glutamatergic excitatory postsynaptic currents (EPSCs) and spontaneous and miniature GABAergic and glycinergic inhibitory postsynaptic currents (sIPSCs and mIPSCs, respectively) were performed in spinal cord slices. The specific group II mGluR agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) had a similar inhibitory effect on monosynaptic EPSCs evoked from the dorsal root in sham and nerve-injured rats. However, DCG-IV produced a greater inhibitory effect on evoked polysynaptic EPSCs and the frequency of spontaneous EPSCs in nerve-injured rats than in control rats. Although DCG-IV similarly reduced the frequency of GABAergic sIPSCs and mIPSCs in both groups, it distinctly inhibited the frequency of glycinergic sIPSCs and mIPSCs only in nerve-injured rats. The DCG-IV effect was blocked by the group II mGluR antagonist but not by the N-methyl-D-aspartate receptor antagonist. Strikingly, intrathecal injection of DCG-IV dose-dependently attenuated allodynia and hyperalgesia in nerve-injured rats but produced hyperalgesia in control rats. Our study provides new information that nerve injury up-regulates group II mGluRs present on glutamatergic and glycinergic interneurons in the spinal cord. Activation of group II mGluRs reduces neuropathic pain probably by attenuating glutamatergic and glycinergic input to spinal dorsal horn neurons.
- Published
- 2011
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223. Sustained inhibition of neurotransmitter release from nontransient receptor potential vanilloid type 1-expressing primary afferents by mu-opioid receptor activation-enkephalin in the spinal cord.
- Author
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Zhou, Hong-Yi, Chen, Shao-Rui, Chen, Hong, and Pan, Hui-Lin
- Abstract
Removing transient receptor potential vanilloid type 1 (TRPV1)-expressing primary afferent neurons reduces presynaptic mu-opioid receptors but potentiates opioid analgesia. However, the sites and underlying cellular mechanisms for this paradoxical effect remain uncertain. In this study, we determined the presynaptic and postsynaptic effects of the mu-opioid receptor agonist [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]-enkephalin (DAMGO) using whole-cell patch-clamp recordings of lamina II neurons in rat spinal cord slices. Treatment with the ultrapotent TRPV1 agonist resiniferotoxin (RTX) eliminated TRPV1-expressing dorsal root ganglion neurons and their central terminals in the spinal dorsal horn and significantly reduced the basal amplitude of glutamatergic excitatory postsynaptic currents (EPSCs) evoked from primary afferents. Although RTX treatment did not significantly alter the concentration-response effect of DAMGO on evoked monosynaptic and polysynaptic EPSCs, it causes a profound long-lasting inhibitory effect of DAMGO on evoked EPSCs. Subsequent naloxone treatment did not reverse the prolonged inhibitory effect of DAMGO on evoked EPSCs. Furthermore, brief application of DAMGO produced a sustained inhibition of miniature EPSCs in RTX-treated rats. However, the concentration response and the duration of the effects of DAMGO on G protein-coupled inwardly rectifying K+ currents in lamina II neurons were not significantly different between vehicle- and RTX-treated groups. These data suggest that stimulation of mu-opioid receptors on non-TRPV1 afferent terminals causes extended inhibition of neurotransmitter release to spinal dorsal horn neurons. The differential effect of mu-opioid receptor agonists on different phenotypes of primary afferents provides a cellular basis to explain why the analgesic action of opioids on mechanonociception is prolonged when TRPV1-expressing primary afferents are removed.
- Published
- 2008
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224. Increased C-fiber nociceptive input potentiates inhibitory glycinergic transmission in the spinal dorsal horn.
- Author
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Zhou, Hong-Yi, Zhang, Hong-Mei, Chen, Shao-Rui, and Pan, Hui-Lin
- Abstract
Glycine is an important inhibitory neurotransmitter in the spinal cord, but it also acts as a coagonist at the glycine site of N-methyl-d-aspartate (NMDA) receptors to potentiate nociceptive transmission. However, little is known about how increased nociceptive inflow alters synaptic glycine release in the spinal dorsal horn and its functional significance. In this study, we performed whole-cell recordings in rat lamina II neurons to record glycinergic spontaneous inhibitory postsynaptic currents (sIPSCs). The transient receptor potential vanilloid receptor 1 agonist capsaicin caused a prolonged increase in the frequency of sIPSCs in 17 of 25 (68%) neurons tested. The potentiating effect of capsaicin on sIPSCs was blocked by ionotropic glutamate receptor antagonists or tetrodotoxin in most lamina II neurons examined. In contrast, the P2X agonist alphabeta-methylene-ATP increased sIPSCs in only two of 16 (12.5%) neurons. The glutamate transporter inhibitor l-trans-pyrrolidine-2,4-dicarboxylic acid either increased or reduced the basal frequency of sIPSCs but did not significantly alter the potentiating effect of capsaicin on sIPSCs. Furthermore, the groups II and III metabotropic glutamate receptor antagonists had no significant effect on the capsaicin-induced increase in the sIPSC frequency. Although capsaicin reduced the amplitude of evoked excitatory postsynaptic currents at high stimulation currents, it did not change the ratio of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/NMDA currents. This study provides the important new information that increased nociceptive inflow augments synaptic glycine release to spinal dorsal horn neurons through endogenous glutamate release. Potentiation of inhibitory glycinergic tone by stimulation of nociceptive primary afferents may function as a negative feedback mechanism to attenuate nociceptive transmission at the spinal level.
- Published
- 2008
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225. Role of Presynaptic Muscarinic and GABABReceptors in Spinal Glutamate Release and Cholinergic Analgesia in Rats
- Author
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Li, De‐Pei, Chen, Shao‐Rui, Pan, Yu‐Zhen, Levey, Allan I., and Pan, Hui‐Lin
- Abstract
Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors can produce effective pain relief. However, the analgesic mechanisms and the site of actions of cholinergic agents in the spinal cord are not fully understood. In this study, we investigated the mechanisms underlying cholinergic presynaptic regulation of glutamate release onto spinal dorsal horn neurons. The role of spinal GABABreceptors in the antinociceptive action of muscarine was also determined. Whole‐cell voltage‐clamp recordings were performed on visualized dorsal horn neurons in the lamina II in the spinal cord slice preparation of rats. The miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) were recorded in the presence of tetrodotoxin. The evoked EPSCs (eEPSCs) were obtained by electrical stimulation of the dorsal root entry zone or the attached dorsal root. Nociception in rats was measured using a radiant heat stimulus and the effect of intrathecal administration of drugs tested. Acetylcholine (10–100 μM) reduced the amplitude of monosynaptic eEPSCs in a concentration‐dependent manner. Acetylcholine also significantly decreased the frequency of non‐NMDA receptor‐mediated mEPSCs, which was antagonized by atropine but not mecamylamine. The frequency of GABAAreceptor‐mediated mIPSCs was significantly increased by acetylcholine and this excitatory effect was abolished by atropine. Existence of presynaptic M2muscarinic receptors in the spinal dorsal horn was further demonstrated by immunocytochemistry staining and dorsal rhizotomy. CGP55845, a GABABreceptor antagonist, significantly attenuated the inhibitory effect of acetylcholine on the frequency of mEPSCs and the amplitude of monosynaptic eEPSCs in lamina II neurons. Furthermore, the antinociceptive action produced by intrathecal muscarine was significantly reduced by CGP55845 pretreatment in rats. Therefore, data from this integrated study provide new information that acetylcholine inhibits the glutamatergic synaptic input to lamina II neurons through presynaptic muscarinic receptors. Inhibition of glutamate release onto lamina II neurons by presynaptic muscarinic and GABABheteroreceptors in the spinal cord probably contributes to the antinociceptive action of cholinergic agents.
- Published
- 2002
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226. α2δ‐1 protein promotes synaptic expression of Ca2+ permeable–AMPA receptors by inhibiting GluA1/GluA2 heteromeric assembly in the hypothalamus in hypertension.
- Author
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Zhou, Jing‐Jing, Shao, Jian‐Ying, Chen, Shao‐Rui, Chen, Hong, and Pan, Hui‐Lin
- Subjects
- *
HYPOTHALAMUS , *RECEPTOR-interacting proteins , *AUTONOMIC nervous system , *AMPA receptors , *PARAVENTRICULAR nucleus , *GLUTAMATE receptors - Abstract
Glutamate AMPA receptors (AMPARs) lacking GluA2 subunit are calcium permeable (CP‐AMPARs), which are increased in the hypothalamic paraventricular nucleus (PVN) and maintain sympathetic outflow in hypertension. Here, we determined the role of α2δ‐1, an NMDA receptor–interacting protein, in regulating synaptic CP‐AMPARs in the hypothalamus in spontaneously hypertensive rats (SHR). Co‐immunoprecipitation showed that levels of GluA1/GluA2, but not GluA2/GluA3, protein complexes in hypothalamic synaptosomes were reduced in SHR compared with Wistar–Kyoto rats (WKY). The level of GluA1/GluA2 heteromers in endoplasmic reticulum‐enriched fractions of the hypothalamus was significantly lower in SHR than in WKY, which was restored by inhibiting α2δ‐1 with gabapentin. Gabapentin also switched AMPAR‐mediated excitatory postsynaptic currents (AMPAR‐EPSCs) from inward rectifying to linear and attenuated the inhibitory effect of IEM‐1460, a selective CP‐AMPAR blocker, on AMPAR‐EPSCs in spinally projecting PVN neurons in SHR. Furthermore, co‐immunoprecipitation revealed that α2δ‐1 directly interacted with GluA1 and GluA2 in the hypothalamus of rats and humans. Levels of α2δ‐1/GluA1 and α2δ‐1/GluA2 protein complexes in the hypothalamus were significantly greater in SHR than in WKY. Disrupting the α2δ‐1–AMPAR interaction with an α2δ‐1 C terminus peptide normalized GluA1/GluA2 heteromers in the endoplasmic reticulum of the hypothalamus diminished in SHR. In addition, α2δ‐1 C terminus peptide diminished inward rectification of AMPAR‐EPSCs and the inhibitory effect of IEM‐1460 on AMPAR‐EPSCs of PVN neurons in SHR. Thus, α2δ‐1 augments synaptic CP‐AMPARs by inhibiting GluA1/GluA2 heteromeric assembly in the hypothalamus in hypertension. These findings extend our understanding of the molecular basis of sustained sympathetic outflow in neurogenic hypertension. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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227. μ-Opioid receptors in primary sensory neurons are involved in supraspinal opioid analgesia.
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Sun, Jie, Chen, Shao-Rui, and Pan, Hui-Lin
- Subjects
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SENSORY neurons , *SENSORY receptors , *OPIOID receptors , *PRESYNAPTIC receptors , *OPIOID peptides - Abstract
• The spinal dorsal horn is a key site for descending inhibition and opioid analgesia. • Blocking spinal opioid receptors diminishes supraspinal opioid analgesic effects. • Opioid receptor ablation in primary sensory neurons reduces supraspinal analgesia. • Presynaptic opioid receptors in spinal cords mediate supraspinal opioid analgesia. Both inhibiting ascending nociceptive transmission and activating descending inhibition are involved in the opioid analgesic effect. The spinal dorsal horn is a critical site for modulating nociceptive transmission by descending pathways elicited by opioids in the brain. μ-Opioid receptors (MORs, encoded by Oprm1) are highly expressed in primary sensory neurons and their central terminals in the spinal cord. In the present study, we tested the hypothesis that MORs expressed in primary sensory neurons contribute to the descending inhibition and supraspinal analgesic effect induced by centrally administered opioids. We generated Oprm1 conditional knockout (Oprm1 -cKO) mice by crossing Advillin Cre/+ mice with Oprm1 flox/flox mice. Immunocytochemical labeling in Oprm1 -cKO mice showed that MORs are completely ablated from primary sensory neurons and are profoundly reduced in the superficial spinal dorsal horn. Intracerebroventricular injection of morphine or fentanyl produced a potent analgesic effect in wild-type mice, but such an effect was significantly attenuated in Oprm1 -cKO mice. Furthermore, the analgesic effect produced by morphine or fentanyl microinjected into the periaqueductal gray was significantly greater in wild-type mice than in Oprm1 -cKO mice. Blocking MORs at the spinal cord level diminished the analgesic effect of morphine and fentanyl microinjected into the periaqueductal gray in both groups of mice. Our findings indicate that MORs expressed at primary afferent terminals in the spinal cord contribute to the supraspinal opioid analgesic effect. These presynaptic MORs in the spinal cord may serve as an interface between ascending inhibition and descending modulation that are involved in opioid analgesia. [ABSTRACT FROM AUTHOR]
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- 2020
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228. ChemInform Abstract: An Efficient Three-Component Synthesis of Trispiropyrrolidines Derivatives Through 1,3-Dipolar Cycloaddition Reaction.
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Feng, Guo‐Liang, Li, Yue, Chen, Shao‐Rui, Geng, Li‐Jun, and Wang, Kai‐Fang
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- 2015
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229. Transcriptional Regulation of Potassium Channel Expression by G9a in Neuropathic Pain
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Pan, Hui-Lin, Chen, Shao-Rui, Laumet, Geoffroy, and Zhang, Yuhao
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- 2016
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230. An efficient three-component synthesis of trispiropyrrolidines derivatives through 1,3-dipolar cycloaddition reaction.
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Feng, Guo-Liang, Li, Yue, Chen, Shao-Rui, Geng, Li-Jun, and Wang, Kai-Fang
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RING formation (Chemistry) , *INDOLE , *ISATIN , *TOLUENE , *NUCLEAR magnetic resonance - Abstract
The synthesis of novel trispiropyrrolidine derivatives has been achieved by a one-pot, three-component 1,3-dipolar cycloaddition reaction of 3-aryl-5-arylmethylenespiro[indole-3′,2-[1,3]thiazolane]-2′(1H),4-dione, isatin and sarcosine in refluxing toluene which produced the corresponding cycloadducts in good yields. The structures were determined by 1 H NMR, IR and elementary analysis. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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231. Calcineurin inhibition causes persistent hypertension through hypothalamic NMDA receptor‐dependent sympathetic outflow.
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Zhou, Jing‐Jing, Shao, Jian‐Ying, Chen, Shao‐Rui, and Pan, Hui‐Lin
- Abstract
R601 --> 715.1 --> Calcineurin is a calcium/calmodulin‐dependent serine/threonine protein phosphatase, and hypertension is a major side effect of clinically used calcineurin inhibitors. Although increased sympathetic nerve discharges are associated with calcineurin inhibitor‐induced hypertension, the sources of sympathetic outflow are unknown. In this study, we determined the role of the paraventricular nuclear (PVN) of the hypothalamus in calcineurin inhibitor‐induced hypertension. Immunocytochemistry labeling showed that calcineurin was expressed on spinally projecting PVN neurons. Radiotelemetry recordings showed that systemic administration of tacrolimus (FK506), a specific calcineurin inhibitor, for 14 days caused a gradual and significant increase in arterial blood pressure in rats, which lasted at least another 7 days after discontinuing FK506 treatment. FK506 significantly decreased calcineurin activity in the PVN and increased the protein level of GluN1, the NMDA receptor obligatory subunit, and serine/threonine phosphorylation levels of GluN1 in the PVN synaptosomes. Electrophysiological recordings revealed that the spontaneous firing rate, frequency of mEPSCs, and amplitude of puff NMDA‐elicited currents in spinally projecting PVN neurons were significant greater in FK506‐treated rats than in vehicle‐treated rats. Remarkably, treatment with the NMDA receptor antagonist AP5 normalized the stimulatory effects of FK506 on PVN neurons of FK506‐treated rats. Furthermore, microinjection of AP5 into the PVN decreased renal sympathetic nerve discharges and blood pressure increased in FK506‐treated rats. Systemic administration of memantine, a clinically used NMDA receptor antagonist, also significantly lowered the high blood pressure in FK506‐treated rats. Collectively, our findings indicate that calcineurin inhibitor‐induced persistent hypertension results from augmented sympathetic output through increased NMDA receptor phosphorylation and activity in the PVN. [ABSTRACT FROM AUTHOR]
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- 2022
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232. Mastering tricyclic ring systems for desirable functional cannabinoid activity.
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Petrov, Ravil R., Knight, Lindsay, Chen, Shao-Rui, Wager-Miller, Jim, McDaniel, Steven W., Diaz, Fanny, Barth, Francis, Pan, Hui-Lin, Mackie, Ken, Cavasotto, Claudio N., and Diaz, Philippe
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CANNABINOID receptors , *PAIN management , *CARBAZOLE , *CHEMICAL synthesis , *SERUM albumin , *ETHYLENEDIAMINETETRAACETIC acid , *GUANOSINE triphosphatase - Abstract
Abstract: There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain and other indications. In continuation of our ongoing program aiming for the development of new small molecule cannabinoid ligands, we have synthesized a novel series of carbazole and γ-carboline derivatives. The affinities of the newly synthesized compounds were determined by a competitive radioligand displacement assay for human CB2 cannabinoid receptor and rat CB1 cannabinoid receptor. Functional activity and selectivity at human CB1 and CB2 receptors were characterized using receptor internalization and [35S]GTP-γ-S assays. The structure–activity relationship and optimization studies of the carbazole series have led to the discovery of a non-selective CB1 and CB2 agonist, compound 4. Our subsequent research efforts to increase CB2 selectivity of this lead compound have led to the discovery of CB2 selective compound 64, which robustly internalized CB2 receptors. Compound 64 had potent inhibitory effects on pain hypersensitivity in a rat model of neuropathic pain. Other potent and CB2 receptor–selective compounds, including compounds 63 and 68, and a selective CB1 agonist, compound 74 were also discovered. In addition, we identified the CB2 ligand 35 which failed to promote CB2 receptor internalization and inhibited compound CP55,940-induced CB2 internalization despite a high CB2 receptor affinity. The present study provides novel tricyclic series as a starting point for further investigations of CB2 pharmacology and pain treatment. [Copyright &y& Elsevier]
- Published
- 2013
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233. Corrigendum to "LRRC8A-dependent volume-regulated anion channels contribute to ischemia-induced brain injury and glutamatergic input to hippocampal neurons" [Experimental Neurology, 332(2020)113391].
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Zhou, Jing-Jing, Luo, Yi, Chen, Shao-Rui, Shao, Jian-Ying, Sah, Rajan, and Pan, Hui-Lin
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BRAIN injuries , *HIPPOCAMPUS (Brain) , *NEURONS , *ANIONS , *NEUROLOGY , *PYRAMIDAL neurons , *ENTORHINAL cortex - Published
- 2022
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234. Distinct intrinsic and synaptic properties of pre-sympathetic and pre-parasympathetic output neurons in Barrington's nucleus.
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Guo, Yue‐Xian, Li, De‐Pei, Chen, Shao‐Rui, and Pan, Hui‐Lin
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NEURAL transmission , *SYMPATHETIC nervous system , *PARASYMPATHETIC nervous system , *GLYCINE receptors , *EXCITATORY amino acid agents , *NEURAL circuitry - Abstract
Barrington's nucleus ( BN), commonly known as the pontine micturition center, controls micturition and other visceral functions through projections to the spinal cord. In this study, we developed a rat brain slice preparation to determine the intrinsic and synaptic mechanisms regulating pre-sympathetic output ( PSO) and pre-parasympathetic output ( PPO) neurons in the BN using patch-clamp recordings. The PSO and PPO neurons were retrogradely labeled by injecting fluorescent tracers into the intermediolateral region of the spinal cord at T13-L1 and S1-S2 levels, respectively. There were significantly more PPO than PSO neurons within the BN. The basal activity and membrane potential were significantly lower in PPO than in PSO neurons, and A-type K+ currents were significantly larger in PPO than in PSO neurons. Blocking A-type K+ channels increased the excitability more in PPO than in PSO neurons. Stimulting μ-opioid receptors inhibited firing in both PPO and PSO neurons. The glutamatergic EPSC frequency was much lower, whereas the glycinergic IPSC frequency was much higher, in PPO than in PSO neurons. Although blocking GABAA receptors increased the excitability of both PSO and PPO neurons, blocking glycine receptors increased the firing activity of PPO neurons only. Furthermore, blocking ionotropic glutamate receptors decreased the excitability of PSO neurons but paradoxically increased the firing activity of PPO neurons by reducing glycinergic input. Our findings indicate that the membrane and synaptic properties of PSO and PPO neurons in the BN are distinctly different. This information improves our understanding of the neural circuitry and central mechanisms regulating the bladder and other visceral organs. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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235. (E)-1-(4-ethoxyphenyl)-3-(4-nitrophenyl)-prop-2-en-1-one suppresses LPS-induced inflammatory response through inhibition of NF-κB signaling pathway.
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Xu, Jian, Jia, Yan-Yan, Chen, Shao-Rui, Ye, Jian-Tao, Bu, Xian-Zhang, Hu, Yun, Ma, Yun-Zi, Guo, Jin-Lei, and Liu, Pei-Qing
- Subjects
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NF-kappa B , *CELLULAR signal transduction , *NITROPHENYL compounds , *INFLAMMATION , *FLAVONOIDS , *PHENYL compounds , *CHINESE medicine , *CARDIOVASCULAR disease treatment - Abstract
Abstract: Flavonoids are a class of compounds that exist in nature with the structure of 2-phenyl-chromone. In Chinese traditional medicine, herbal drugs containing flavonoids are widely used for the treatment of inflammation, cardiovascular disease, tumor and so on. In this study, we investigated the anti-inflammatory effect and related mechanisms of a novel synthetic flavonoid, (E)-1-(4-ethoxyphenyl)-3-(4-nitrophenyl)-prop-2-en-1-one (ETH) in lipopolysaccharide (LPS) stimulated macrophages. Our results showed that ETH inhibited LPS-induced TNF-α and IL-6 release in a dose-dependent manner, and decreased TNF-α, IL-1β, IL-6 and iNOS mRNA production. LPS-induced expression of cyclooxygenase-2 (COX-2) was also significantly attenuated by ETH. Pretreatment with ETH reduced the I-κBα phosphorylation, p65 nuclear translocation as well as NF-κB-dependent transcriptional activity. In addition, ETH exhibited a significant protection against LPS-induced inflammatory mortality in mice. Taken together, these findings suggest that ETH can inhibit LPS-induced inflammation via suppressing NF-κB signaling pathway, indicating that ETH may be a potential anti-inflammatory agent. [Copyright &y& Elsevier]
- Published
- 2013
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236. Nmnat2 protects cardiomyocytes from hypertrophy via activation of SIRT6
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Cai, Yi, Yu, Shan-Shan, Chen, Shao-Rui, Pi, Rong-Biao, Gao, Si, Li, Hong, Ye, Jian-Tao, and Liu, Pei-Qing
- Subjects
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HEART cells , *HYPERTROPHY , *SIRTUINS , *NAD (Coenzyme) , *DEACETYLASES , *BIOSYNTHESIS , *ANGIOTENSIN II , *ATRIAL natriuretic peptides - Abstract
Abstract: The discovery of sirtuins (SIRT), a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, has indicated that intracellular NAD level is crucial for the hypertrophic response of cardiomyocytes. Nicotinamide mononucleotide adenylyltransferase (Nmnat) is a central enzyme in NAD biosynthesis. Here we revealed that Nmnat2 protein expression and enzyme activity were down-regulated during cardiac hypertrophy. In neonatal rat cardiomyocytes, overexpression of Nmnat2 but not its catalytically inactive mutant blocked angiotensin II (Ang II)-induced cardiac hypertrophy, which was dependent on activation of SIRT6 through maintaining the intracellular NAD level. Our results suggested that modulation of Nmnat2 activity may be beneficial in cardiac hypertrophy. [Copyright &y& Elsevier]
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- 2012
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237. Effect of kappa opioid agonists on visceral nociception induced by uterine cervical distension in rats
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Sandner-Kiesling, Andreas, Pan, Hui-Lin, Chen, Shao-Rui, James, Robert L., DeHaven-Hudkins, Diane L., Dewan, David M., and Eisenach, James C.
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UTERINE cervix incompetence , *PAIN , *OPIOID receptors - Abstract
Although uterine distension in rats results in an escape reflex, there exists no model of uterine cervical distension (UCD), the pain stimulus during the first stage of labor. The aims of this study were to develop such a model in virgin rats and to test whether peripherally restricted kappa opioid receptor (KOR) agonists (ADL 10-0101, ADL 10-0102, ADL 10-0116) inhibit responses to UCD. Under intravenous (i.v.) pentobarbital and alpha-chloralose anesthesia, fine metal rods were inserted in both uterine cervical osses through a small midline laparotomy. UCD was performed by manual separation of the rods (25–100 g). Single-unit afferent responses in hypogastric nerve or reflex rectus abdominis electromyographic (EMG) activity were determined before and after i.v. KOR agonists. UCD resulted in a stimulus-dependent increase in single-unit afferent activity. Units could be characterized as low threshold (mean threshold 6.6±2.7 g), or high threshold (mean threshold 55±8.8 g); all were C fibers, all responded to topical bradykinin. ADL 10-0116 (10 mg/kg) reduced the afferent response to UCD. Reflex EMG response occurred over a distension force range of 25–100 g, unaffected by i.v. saline. All three KOR agonists produced a dose-dependent, naloxone-reversible inhibition of the EMG response with a potency relationship of ADL 10-0102 (ED50 0.04 mg/kg)>ADL 10-0101 (ED50 0.65 mg/kg)=ADL 10-0116 (ED50 0.60 mg/kg). These data support the use of acute UCD as a noxious stimulus, inducing afferent and reflex activity. Like other visceral stimuli, UCD is sensitive to inhibition by KOR agonists. [Copyright &y& Elsevier]
- Published
- 2002
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238. LRRC8A-dependent volume-regulated anion channels contribute to ischemia-induced brain injury and glutamatergic input to hippocampal neurons.
- Author
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Zhou, Jing-Jing, Luo, Yi, Chen, Shao-Rui, Shao, Jian-Ying, Sah, Rajan, and Pan, Hui-Lin
- Subjects
- *
BRAIN injuries , *NEURONS , *EXCITATORY postsynaptic potential , *GLUTAMATE receptors , *CEREBRAL ischemia , *CELL size , *METHYL aspartate receptors , *THETA rhythm - Abstract
Volume-regulated anion channels (VRACs) are critically involved in regulating cell volume, and leucine-rich repeat-containing protein 8A (LRRC8A, SWELL1) is an obligatory subunit of VRACs. Cell swelling occurs early after brain ischemia, but it is unclear whether neuronal LRRC8a contributes to ischemia-induced glutamate release and brain injury. We found that Lrrc8a conditional knockout (Lrrc8a -cKO) mice produced by crossing Nestin Cre+/− with Lrrc8a flox+/+ mice died 7–8 weeks of age, indicating an essential role of neuronal LRRC8A for survival. Middle cerebral artery occlusion (MCAO) caused an early increase in LRRC8A protein levels in the hippocampus in wild-type (WT) mice. Whole-cell patch-clamp recording in brain slices revealed that oxygen-glucose deprivation significantly increased the amplitude of VRAC currents in hippocampal CA1 neurons in WT but not in Lrrc8a -cKO mice. Hypotonicity increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in hippocampal CA1 neurons in WT mice, and this was abolished by DCPIB, a VRAC blocker. But in Lrrc8a -cKO mice, hypotonic solution had no effect on the frequency of sEPSCs in these neurons. Furthermore, the brain infarct volume and neurological severity score induced by MCAO were significantly lower in Lrrc8a -cKO mice than in WT mice. In addition, MCAO-induced increases in cleaved caspase-3 and calpain activity, two biochemical markers of neuronal apoptosis and death, in brain tissues were significantly attenuated in Lrrc8a -cKO mice compared with WT mice. These new findings indicate that cerebral ischemia increases neuronal LRRC8A-dependent VRAC activity and that VRACs contribute to increased glutamatergic input to hippocampal neurons and brain injury caused by ischemic stroke. Schematic drawing outlines the potential role of neuronal LRRC8A-containing volume-regulated anion channels (VRACs) in ischemic brain damage. Neuronal VRACs are not activated or involved in glutamate release in the normal brain. Cerebral ischemia causes rapid cell swelling and neuronal depolarization to increase the activity of VRACs expressed in presynaptic and postsynaptic neurons. Augmented VRAC activity in ischemic neurons leads to chloride influx and glutamate release and subsequent activation of glutamate NMDA receptors, which can induce excitotoxicity and neuronal death through calplain/caspase-mediated signaling pathways. Unlabelled Image • Cerebral ischemia transiently increases LRRC8A protein levels in the hippocampus. • LRRC8A is essential for hippocampal neuronal VRAC activity increased by ischemia. • LRRC8A is required for hypotonicity-potentiated glutamatergic input to neurons. • LRRC8A-dependent VRACs contribute to brain injury caused by cerebral ischemia. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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239. δ-Opioid receptors in primary sensory neurons tonically restrain nociceptive input in chronic pain but do not enhance morphine analgesic tolerance.
- Author
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Jin, Daozhong, Chen, Hong, Huang, Yuying, Chen, Shao-Rui, and Pan, Hui-Lin
- Subjects
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SENSORY neurons , *OPIOID receptors , *SENSORY receptors , *PERIPHERAL nervous system , *CHRONIC pain , *DORSAL root ganglia - Abstract
δ-Opioid receptors (DORs, encoded by the Oprd1 gene) are expressed throughout the peripheral and central nervous system, and DOR stimulation reduces nociception. Previous studies suggest that DORs promote the development of analgesic tolerance of μ-opioid receptor (MOR) agonists. It is uncertain whether DORs expressed in primary sensory neurons are involved in regulating chronic pain and MOR agonist-induced tolerance. In this study, we generated Oprd1 conditional knockout (Oprd1 -cKO) mice by crossing Advillin-Cre mice with Oprd1 -floxed mice. DOR expression in the dorsal root ganglion was diminished in Oprd1 -cKO mice. Systemic or intrathecal injection of the DOR agonist SNC-80 produced analgesia in wild-type (WT), but not Oprd1 -cKO, mice. In contrast, intracerebroventricular injection of SNC-80 produced a similar analgesic effect in WT and Oprd1 -cKO mice. However, morphine-induced analgesia, hyperalgesia, or analgesic tolerance did not differ between WT and Oprd1 -cKO mice. Compared with WT mice, Oprd1 -cKO mice showed increased mechanical and heat hypersensitivity after nerve injury or tissue inflammation. Furthermore, blocking DORs with naltrindole increased nociceptive sensitivity induced by nerve injury or tissue inflammation in WT, but not Oprd1 -cKO, mice. In addition, naltrindole potentiated glutamatergic input from primary afferents to spinal dorsal horn neurons increased by nerve injury or CFA in WT mice; this effect was absent in Oprd1 -cKO mice. Our findings indicate that DORs in primary sensory neurons are critically involved in the analgesic effect of DOR agonists but not morphine-induced analgesic tolerance. Presynaptic DORs at primary afferent central terminals constitutively inhibit inflammatory and neuropathic pain by restraining glutamatergic input to spinal dorsal horn neurons. • δ-opioid receptors (DORs) in primary sensory neurons restrain pain hypersensitivity caused by inflammation or nerve injury. • Presynaptic DORs tonically inhibit glutamatergic input to spinal dorsal horn neurons induced by inflammation or nerve injury. • The analgesic effect produced by systemic or intrathecal DOR agonists critically depends on DORs in primary sensory neurons. • Morphine produces analgesia, hyperalgesia, and tolerance independent of DORs expressed in primary sensory neurons. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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240. α-Enolase plays a catalytically independent role in doxorubicin-induced cardiomyocyte apoptosis and mitochondrial dysfunction.
- Author
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Gao, Si, Li, Hong, Feng, Xiao-jun, Li, Min, Liu, Zhi-ping, Cai, Yi, Lu, Jing, Huang, Xiao-yang, Wang, Jiao-jiao, Li, Qin, Chen, Shao-rui, Ye, Jian-tao, and Liu, Pei-qing
- Subjects
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ENOLASE , *DOXORUBICIN , *APOPTOTIC bodies , *APOPTOSIS , *PROGRAMMED cell death 1 receptors - Abstract
Background α-Enolase is a glycolytic enzyme with “second jobs” beyond its catalytic activity. However, its possible contribution to cardiac dysfunction remains to be determined. The present study aimed to investigate the role of α-enolase in doxorubicin (Dox)-induced cardiomyopathy as well as the underlying mechanisms. Experimental approaches The expression of α-enolase was detected in rat hearts and primary cultured rat cardiomyocytes with or without Dox administration. An adenovirus carrying short-hairpin interfering RNA targeting α-enolase was constructed and transduced specifically into the heart by intramyocardial injection. Heart function, cell apoptosis and mitochondrial function were measured following Dox administration. In addition, by using gain- and loss-of-function approaches to regulate α-enolase expression in primary cultured rat cardiomyocytes, we investigated the role of endogenous, wide type and catalytically inactive mutant α-enolase in cardiomyocyte apoptosis and ATP generation. Furthermore, the involvement of α-enolase in AMPK phosphorylation was also studied. Key results The mRNA and protein expression of cardiac α-enolase was significantly upregulated by Dox. Genetic silencing of α-enolase in rat hearts and cultured cardiomyocytes attenuated Dox-induced apoptosis and mitochondrial dysfunction. In contrast, overexpression of wide-type or catalytically inactive α-enolase in cardiomyocytes mimicked the detrimental role of Dox in inducing apoptosis and ATP reduction. AMPK dephosphorylation was further demonstrated to be involved in the proapoptotic and ATP-depriving effects of α-enolase. Conclusion Our findings provided the evidence that α-enolase has a catalytically independent role in inducing cardiomyocyte apoptosis and mitochondrial dysfunction, which could be at least partially contributed to the inhibition of AMPK phosphorylation. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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241. Downregulation of adipose triglyceride lipase promotes cardiomyocyte hypertrophy by triggering the accumulation of ceramides.
- Author
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Gao, Hui, Feng, Xiao-jun, Li, Zhuo-ming, Li, Min, Gao, Si, He, Yan-hong, Wang, Jiao-jiao, Zeng, Si-yu, Liu, Xue-ping, Huang, Xiao-yang, Chen, Shao-rui, and Liu, Pei-qing
- Subjects
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DOWNREGULATION , *ADIPOSE tissues , *TRIGLYCERIDES , *LIPASES , *HEART cells , *HYPERTROPHY , *CERAMIDES - Abstract
Adipose triglyceride lipase (ATGL), the rate-limiting enzyme of triglyceride (TG) hydrolysis, plays an important role in TG metabolism. ATGL knockout mice suffer from TG accumulation and die from heart failure. However, the mechanisms underlying cardiac hypertrophy caused by ATGL dysfunction remain unknown. In this study, we found that ATGL expression declined in pressure overload-induced cardiac hypertrophy in vivo and phenylephrine (PE)-induced cardiomyocyte hypertrophy in vitro . ATGL knockdown led to cardiomyocyte hypertrophy, while ATGL overexpression prevented PE-induced hypertrophy. In addition, ATGL downregulation increased but ATGL overexpression reduced the contents of ceramide, which has been proved to be closely associated with cardiac hypertrophy. Moreover, the accumulation of ceramide was due to elevation of free fatty acids in ATGL-knockdown cardiomyocytes, which could be explained by the reduced activity of peroxisome proliferator-activated receptor (PPAR) α leading to imbalance of fatty acid uptake and oxidation. These observations suggest that downregulation of ATGL causes the decreased PPARα activity which results in the imbalance of FA uptake and oxidation, elevating intracellular FFA contents to promote the accumulation of ceramides, and finally inducing cardiac hypertrophy. Upregulation of ATGL could be a strategy for ameliorating lipotoxic damage in cardiac hypertrophy. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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242. Hyper-SUMOylation of the Kv7 Potassium Channel Diminishes the M-Current Leading to Seizures and Sudden Death.
- Author
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Qi, Yitao, Wang, Jingxiong, Bomben, Valerie C., Li, De-Pei, Chen, Shao-Rui, Sun, Hao, Xi, Yutao, Reed, John G., Cheng, Jinke, Pan, Hui-Lin, Noebels, Jeffrey L., and Yeh, Edward T.H.
- Subjects
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POST-translational modification , *POTASSIUM channels , *SPASMS , *SUDDEN death , *ANIMAL models in research , *ATRIOVENTRICULAR node - Abstract
Summary Sudden unexplained death in epilepsy (SUDEP) is the most common cause of premature mortality in epilepsy and was linked to mutations in ion channels; however, genes within the channel protein interactome might also represent pathogenic candidates. Here we show that mice with partial deficiency of Sentrin/SUMO-specific protease 2 (SENP2) develop spontaneous seizures and sudden death. SENP2 is highly enriched in the hippocampus, often the focus of epileptic seizures. SENP2 deficiency results in hyper-SUMOylation of multiple potassium channels known to regulate neuronal excitability. We demonstrate that the depolarizing M-current conducted by Kv7 channel is significantly diminished in SENP2-deficient hippocampal CA3 neurons, primarily responsible for neuronal hyperexcitability. Following seizures, SENP2-deficient mice develop atrioventricular conduction blocks and cardiac asystole. Both seizures and cardiac conduction blocks can be prevented by retigabine, a Kv7 channel opener. Thus, we uncover a disease-causing role for hyper-SUMOylation in the nervous system and establish an animal model for SUDEP. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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243. Sirtuin 6 protects cardiomyocytes from hypertrophy in vitro via inhibition of NF-κB-dependent transcriptional activity.
- Author
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Yu SS, Cai Y, Ye JT, Pi RB, Chen SR, Liu PQ, Shen XY, Ji Y, Yu, Shan-Shan, Cai, Yi, Ye, Jian-Tao, Pi, Rong-Biao, Chen, Shao-Rui, Liu, Pei-Qing, Shen, Xiao-Yan, and Ji, Yong
- Abstract
Background and Purpose: Sirtuin 6 (SIRT6) is involved in regulation of glucose and fat metabolism. However, its possible contribution to cardiac dysfunction remains to be determined. In the present study, the effect of SIRT6 on cardiac hypertrophy induced by angiotensin II (AngII) and the underlying molecular mechanisms were investigated.Experimental Approach: The expression and deacetylase activity of SIRT6 were measured in hypertrophic cardiomyocytes induced by AngII. After SIRT6 overexpression by transfection, or depletion by RNA interference in neonatal rat cardiomyocytes, cellular hypertrophy was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Further, the interaction between SIRT6 and the transcription factor NF-κB was investigated by co-immunoprecipitation, confocal immunofluorescence microscopy and luciferase reporter gene assay. The expression and deacetylase activity of SIRT6 were measured in vivo, using the abdominal aortic constriction (AAC) model of cardiac hypertrophy in rats.Key Results: In AngII-induced hypertrophic cardiomyocytes and also in AAC-induced hypertrophic hearts, the expression of SIRT6 protein was upregulated, while its deacetylase activity was decreased. Overexpression of wild-type SIRT6 but not its catalytically inactive mutant, attenuated AngII-induced cardiomyocyte hypertrophy. We further demonstrated a physical interaction between SIRT6 and NF-κB catalytic subunit p65, whose transcriptional activity could be repressed by SIRT6 overexpression.Conclusions and Implications: Our findings suggest that SIRT6 suppressed cardiomyocyte hypertrophy in vitro via inhibition of NF-κB-dependent transcriptional activity and that this effect was dependent on its deacetylase activity. [ABSTRACT FROM AUTHOR]- Published
- 2013
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244. Cryptotanshinone Suppressed Inflammatory Cytokines Secretion in RAW264.7 Macrophages through Inhibition of the NF-κB and MAPK Signaling Pathways.
- Author
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Tang, Shu, Shen, Xiao-Yan, Huang, He-Qing, Xu, Suo-Wen, Yu, Yang, Zhou, Chang-Hua, Chen, Shao-Rui, Le, Kang, Wang, Yu-Hua, and Liu, Pei-Qing
- Subjects
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CYTOKINES , *MACROPHAGES , *HERBS , *ANTIOXIDANTS , *ANTI-inflammatory agents , *POLYSACCHARIDES , *ENZYME-linked immunosorbent assay , *TUMOR necrosis factors , *PHOSPHORYLATION , *INTERLEUKIN-6 - Abstract
Cryptotanshinone (CTS), a major constituent extracted from the medicinal herb Salvia miltiorrhiza Bunge, has well-documented antioxidative and anti-inflammatory effects. In the present study, the pharmacological effects and underlying molecular mechanisms of CTS on lipopolysaccharide (LPS)-induced inflammatory responses were investigated. By enzyme-linked immunosorbent assay, we observed that CTS reduced significantly the production of proinflammatory mediators (tumor necrosis factor-α and interleukin-6) induced by LPS in murine macrophage-like RAW264.7 cells. Mechanistically, CTS inhibited markedly the phosphorylation of mitogen-activated protein kinases (MAPKs), including ERK1/2, p38MAPK, and JNK, which are crucially involved in regulation of proinflammatory mediator secretion. Moreover, immunofluorescence and western blot analysis indicated that CTS abolished completely LPS-triggered nuclear factor-κB (NF-κB) activation. Taken together, these data implied that NF-κB and MAPKs might be the potential molecular targets for clarifying the protective effects of CTS on LPS-induced inflammatory cytokine production in macrophages. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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245. Modulation of pain transmission by G-protein-coupled receptors
- Author
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Pan, Hui-Lin, Wu, Zi-Zhen, Zhou, Hong-Yi, Chen, Shao-Rui, Zhang, Hong-Mei, and Li, De-Pei
- Subjects
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CENTRAL nervous system , *NERVOUS system , *AMINO acids , *GASTROINTESTINAL hormones - Abstract
Abstract: The heterotrimeric G-protein-coupled receptors (GPCR) represent the largest and most diverse family of cell surface receptors and proteins. GPCR are widely distributed in the peripheral and central nervous systems and are one of the most important therapeutic targets in pain medicine. GPCR are present on the plasma membrane of neurons and their terminals along the nociceptive pathways and are closely associated with the modulation of pain transmission. GPCR that can produce analgesia upon activation include opioid, cannabinoid, α2-adrenergic, muscarinic acetylcholine, γ-aminobutyric acidB (GABAB), groups II and III metabotropic glutamate, and somatostatin receptors. Recent studies have led to a better understanding of the role of these GPCR in the regulation of pain transmission. Here, we review the current knowledge about the cellular and molecular mechanisms that underlie the analgesic actions of GPCR agonists, with a focus on their effects on ion channels expressed on nociceptive sensory neurons and on synaptic transmission at the spinal cord level. [Copyright &y& Elsevier]
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- 2008
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246. Differential responses of regional sympathetic activity and blood flow to visceral afferent stimulation.
- Author
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Pan, Hui-Lin, Deal, Dwight D., Xu, Zemin, and Chen, Shao-Rui
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BLOOD flow , *SYMPATHETIC nervous system , *CAT physiology - Abstract
Presents information on a study which examined changes in regional sympathetic nerve activity and blood flows in anesthesized cats. Materials and methods; Mean arterial blood pressure and heart rate in all animals studied during the control; Alterations of tissue blood flows induced by afferent stimulation.
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- 2001
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247. Group III metabotropic glutamate receptors regulate hypothalamic presympathetic neurons through opposing presynaptic and postsynaptic actions in hypertension.
- Author
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Zhou, Jing-Jing, Pachuau, Judith, Li, De-Pei, Chen, Shao-Rui, and Pan, Hui-Lin
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GLUTAMATE receptors , *HYPOTHALAMUS , *NEURONS , *AUTONOMIC nervous system , *PARAVENTRICULAR nucleus , *BLOOD pressure , *G proteins - Abstract
The hypothalamic paraventricular nucleus (PVN) plays a major role in generating increased sympathetic output in hypertension. Although group III metabotropic glutamate receptors (mGluRs) are expressed in the hypothalamus, little is known about their contribution to regulating PVN presympathetic neurons in hypertension. Here we show that activating group III mGluRs with L-2-amino-4-phosphonobutyric acid (L-AP4) consistently inhibited the firing activity of spinally projecting PVN neurons in normotensive rats. However, in spontaneously hypertensive rats (SHRs), L-AP4 inhibited 45% of PVN neurons but excited 37%. L-AP4 significantly reduced glutamatergic and GABAergic input to PVN neurons in both groups. Blocking postsynaptic G protein signaling eliminated the excitatory but not the inhibitory effect of L-AP4 on PVN neurons in SHRs. Remarkably, prior activation of group I mGluRs converted the L-AP4 effect from inhibitory to excitatory in PVN neurons, and L-AP4 consistently inhibited PVN neurons when mGluR5 was blocked in SHRs. Furthermore, the expression level of mGluR4 and mGluR6 in the PVN was significantly higher in SHRs than in normotensive rats. Microinjection of L-AP4 into the PVN decreased blood pressure and lumbar sympathetic nerve discharges in normotensive rats and SHRs. Additionally, blocking group I mGluRs in the PVN potentiated L-AP4's sympathoinhibitory effect in SHRs. Therefore, activation of presynaptic group III mGluRs inhibits the excitability of PVN presympathetic neurons to attenuate sympathetic vasomotor activity. Through crosstalk with mGluR5, postsynaptic group III mGluR stimulation paradoxically excites PVN presympathetic neurons in SHRs. Concurrently blocking mGluR5 and activating group III mGluRs in the PVN can effectively reduce sympathetic outflow in hypertension. • Group III mGluR stimulation inhibits hypothalamic neurons in normotension but excite some of these neurons in hypertension. • Group III mGluR activation reduces excitatory and inhibitory synaptic inputs to hypothalamic neurons in both conditions. • Group III mGluR stimulation paradoxically excites some hypothalamic neurons in hypertension through postsynaptic mGluR5. • Hypothalamic group III mGluR activation reduces sympathetic output, which is enhanced by blocking mGluR5 in hypertension. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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248. Memantine Inhibits Calcium-Permeable AMPA Receptors.
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Carrillo E, Montaño Romero A, Gonzalez CU, Turcu AL, Chen SR, Chen H, Pan HL, Vázquez S, Twomey EC, and Jayaraman V
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Memantine is an US Food and Drug Administration (FDA) approved drug that selectively inhibits NMDA-subtype ionotropic glutamate receptors (NMDARs) for treatment of dementia and Alzheimer's. NMDARs enable calcium influx into neurons and are critical for normal brain function. However, increasing evidence shows that calcium influx in neurological diseases is augmented by calcium-permeable AMPA-subtype ionotropic glutamate receptors (AMPARs). Here, we demonstrate that these calcium-permeable AMPARs (CP-AMPARs) are inhibited by memantine. Electrophysiology unveils that memantine inhibition of CP-AMPARs is dependent on their calcium permeability and the presence of their neuronal auxiliary subunit transmembrane AMPAR regulatory proteins (TARPs). Through cryo-electron microscopy we elucidate that memantine blocks CP-AMPAR ion channels in a unique mechanism of action from NMDARs. Furthermore, we demonstrate that memantine reverses a gain of function AMPAR mutation found in a patient with a neurodevelopmental disorder and inhibits CP-AMPARs in nerve injury. Our findings alter the paradigm for the memantine mechanism of action and provide a blueprint for therapeutic approaches targeting CP-AMPARs., Competing Interests: Conflict of interest statement: The authors declare no competing financial interests.
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- 2024
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249. Calcineurin regulates synaptic Ca 2+ -permeable AMPA receptors in hypothalamic presympathetic neurons via α2δ-1-mediated GluA1/GluA2 assembly.
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Zhou JJ, Shao JY, Chen SR, Chen H, and Pan HL
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- Animals, Male, Rats, Calcium metabolism, Excitatory Postsynaptic Potentials physiology, Excitatory Postsynaptic Potentials drug effects, Calcineurin Inhibitors pharmacology, Synapses physiology, Synapses drug effects, Synapses metabolism, Receptors, AMPA metabolism, Receptors, AMPA physiology, Calcineurin metabolism, Tacrolimus pharmacology, Neurons physiology, Neurons drug effects, Neurons metabolism, Rats, Sprague-Dawley, Paraventricular Hypothalamic Nucleus physiology, Paraventricular Hypothalamic Nucleus metabolism, Paraventricular Hypothalamic Nucleus drug effects
- Abstract
Hypertension is a major adverse effect of calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, used clinically as immunosuppressants. Calcineurin inhibitor-induced hypertension (CIH) is linked to augmented sympathetic output from the hypothalamic paraventricular nucleus (PVN). GluA2-lacking, Ca
2+ -permeable AMPA receptors (CP-AMPARs) are a key feature of glutamatergic synaptic plasticity, yet their role in CIH remains elusive. Here, we found that systemic administration of FK506 in rats significantly increased serine phosphorylation of GluA1 and GluA2 in PVN synaptosomes. Strikingly, FK506 treatment reduced GluA1/GluA2 heteromers in both synaptosomes and endoplasmic reticulum-enriched fractions from the PVN. Blocking CP-AMPARs with IEM-1460 induced a larger reduction of AMPAR-mediated excitatory postsynaptic current (AMPAR-EPSC) amplitudes in retrogradely labelled, spinally projecting PVN neurons in FK506-treated rats than in vehicle-treated rats. Furthermore, FK506 treatment shifted the current-voltage relationship of AMPAR-EPSCs from linear to inward rectification in labelled PVN neurons. FK506 treatment profoundly enhanced physical interactions of α2δ-1 with GluA1 and GluA2 in the PVN. Inhibiting α2δ-1 with gabapentin, α2δ-1 genetic knockout, or disrupting α2δ-1-AMPAR interactions with an α2δ-1 C terminus peptide restored GluA1/GluA2 heteromers in the PVN and diminished inward rectification of AMPAR-EPSCs in labelled PVN neurons induced by FK506 treatment. Additionally, microinjection of IEM-1460 or α2δ-1 C terminus peptide into the PVN reduced renal sympathetic nerve discharges and arterial blood pressure elevated in FK506-treated rats but not in vehicle-treated rats. Thus, calcineurin in the hypothalamus constitutively regulates AMPAR subunit composition and phenotypes by controlling GluA1/GluA2 interactions with α2δ-1. Synaptic CP-AMPARs in PVN presympathetic neurons contribute to augmented sympathetic outflow in CIH. KEY POINTS: Systemic treatment with the calcineurin inhibitor increases serine phosphorylation of synaptic GluA1 and GluA2 in the PVN. Calcineurin inhibition enhances the prevalence of postsynaptic Ca2+ -permeable AMPARs in PVN presympathetic neurons. Calcineurin inhibition potentiates α2δ-1 interactions with GluA1 and GluA2, disrupting intracellular assembly of GluA1/GluA2 heterotetramers in the PVN. Blocking Ca2+ -permeable AMPARs or α2δ-1-AMPAR interactions in the PVN attenuates sympathetic outflow augmented by the calcineurin inhibitor., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)- Published
- 2024
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250. DNA demethylation in the hypothalamus promotes transcription of Agtr1a and Slc12a2 and hypertension development.
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Ghosh K, Zhou JJ, Shao JY, Chen SR, and Pan HL
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- Animals, Rats, Blood Pressure, DNA metabolism, Hypertension metabolism, Paraventricular Hypothalamic Nucleus metabolism, Rats, Inbred SHR, Rats, Inbred WKY, RNA, Messenger genetics, Sympathetic Nervous System metabolism, DNA Demethylation, Hypothalamus metabolism, Receptor, Angiotensin, Type 1 metabolism, Solute Carrier Family 12, Member 2 metabolism
- Abstract
Increased expression of angiotensin II AT
1A receptor (encoded by Agtr1a) and Na+ -K+ -Cl- cotransporter-1 (NKCC1, encoded by Slc12a2) in the hypothalamic paraventricular nucleus (PVN) contributes to hypertension development. However, little is known about their transcriptional control in the PVN in hypertension. DNA methylation is a critical epigenetic mechanism that regulates gene expression. Here, we determined whether transcriptional activation of Agtr1a and Slc12a2 results from altered DNA methylation in spontaneously hypertensive rats (SHR). Methylated DNA immunoprecipitation and bisulfite sequencing-PCR showed that CpG methylation at Agtr1a and Slc12a2 promoters in the PVN was progressively diminished in SHR compared with normotensive Wistar-Kyoto rats (WKY). Chromatin immunoprecipitation-quantitative PCR revealed that enrichment of DNA methyltransferases (DNMT1 and DNMT3A) and methyl-CpG binding protein 2, a DNA methylation reader protein, at Agtr1a and Slc12a2 promoters in the PVN was profoundly reduced in SHR compared with WKY. By contrast, the abundance of ten-eleven translocation enzymes (TET1-3) at Agtr1a and Slc12a2 promoters in the PVN was much greater in SHR than in WKY. Furthermore, microinjecting of RG108, a selective DNMT inhibitor, into the PVN of WKY increased arterial blood pressure and correspondingly potentiated Agtr1a and Slc12a2 mRNA levels in the PVN. Conversely, microinjection of C35, a specific TET inhibitor, into the PVN of SHR markedly reduced arterial blood pressure, accompanied by a decrease in Agtr1a and Slc12a2 mRNA levels in the PVN. Collectively, our findings suggest that DNA hypomethylation resulting from the DNMT/TET switch at gene promoters in the PVN promotes transcription of Agtr1a and Slc12a2 and hypertension development., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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