Activation of mGluR1 contributes to neuronal hyperexcitability in the rat anterior cingulate cortex via inhibition of HCN channels

Gao, Shi-Hao; Han, Wen; Shen, Lin‐Lin; Zhao, Yandong; Ruan, Han‐Li

doi:10.1016/j.neuropharm.2016.01.036

Cited by 31 publications

(17 citation statements)

References 81 publications

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“…Recently we found that neuropathic pain causes a functional downregulation of hyperpolarization-activated-and-cyclic-nucleotide-regulated (HCN) channels in the dendrites of layer 5 (L5) pyramidal neurons in the ACC leading to cellular hyperexcitability due to enhanced dendritic integration of excitatory postsynaptic potentials (EPSPs) ( Santello and Nevian, 2015 ). This malfunction of HCN channels in pyramidal neurons in the chronic pain condition was recently confirmed by a number of studies ( Cordeiro Matos et al, 2015 , Gao et al, 2016 ).…”

Section: Introductionsupporting

confidence: 52%

The brain-penetrant 5-HT 7 receptor agonist LP-211 reduces the sensory and affective components of neuropathic pain

Santello

Bisco

Nevian

et al. 2017

Neurobiology of Disease

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Neuropathic pain is a debilitating pathological condition of high clinical relevance. Changes in neuronal excitability in the anterior cingulate cortex (ACC) play a central role in the negative emotional and affective aspects of chronic pain. We evaluated the effects of LP-211, a new serotonin-receptor-type-7 (5-HT7R) agonist that crosses the blood-brain barrier, on ACC neurons in a mouse model of neuropathic pain. LP-211 reduced synaptic integration in layer 5 pyramidal neurons, which was enhanced in neuropathic pain due to a dysfunction of dendritic hyperpolarization-activated-and-cyclic-nucleotide-regulated (HCN) channels. Acute injection of LP-211 had an analgesic effect, increasing the mechanical withdrawal threshold in neuropathic animals, which was partially mediated by an action in the ACC. Additionally, the acute application of LP-211 blocked the switch in the place escape/avoidance behavior induced by noxious stimuli. Thus systemic treatment with a 5-HT7R agonist leads to modulation of the ACC, which dampens sensory and affective aspects of chronic pain.

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Section: Introductionsupporting

confidence: 52%

The brain-penetrant 5-HT 7 receptor agonist LP-211 reduces the sensory and affective components of neuropathic pain

Santello

Bisco

Nevian

et al. 2017

Neurobiology of Disease

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“…Recently, the firing activity of layer V ACC neurons by whole‐cell current–clamp recordings in brain slices following chronic constriction injury has been carried out with the aim of assessing the effect of neuropathic pain in the brain. Data stemming from these studies provide strong evidence supporting the fact that mGluR1 is upregulated and activated after peripheral nerve injury, inducing neuronal hyperexcitability through the inhibition of HCN1 in ACC neurons (Gao et al, ). Along similar lines, another study also reported that CCI nerve injury causes strengthening of the intrinsic excitability of pyramidal neurons in ACC (Blom et al, ).…”

Section: Neuroplasticity Of the Cortex With Neuropathic Pain And Inflmentioning

confidence: 83%

Neuroplasticity of Supraspinal Structures Associated with Pathological Pain

Boadas-Vaello

Homs

Reina

et al. 2017

The Anatomical Record

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Peripheral nerve and spinal cord injuries, along with other painful syndromes such as fibromyalgia, diabetic neuropathy, chemotherapeutic neuropathy, trigeminal neuralgia, complex regional pain syndrome, and/or irritable bowel syndrome, cause several neuroplasticity changes in the nervous system along its entire axis affecting the different neuronal nuclei. This paper reviews these changes, focusing on the supraspinal structures that are involved in the modulation and processing of pain, including the periaqueductal gray matter, red nucleus, locus coeruleus, rostral ventromedial medulla, thalamus, hypothalamus, basal ganglia, cerebellum, habenula, primary, and secondary somatosensory cortex, motor cortex, mammillary bodies, hippocampus, septum, amygdala, cingulated, and prefrontal cortex. Hyperexcitability caused by the modification of postsynaptic receptor expression, central sensitization, and potentiation of presynaptic delivery of neurotransmitters, as well as the reduction of inhibitory inputs, changes in dendritic spine, neural circuit remodeling, alteration of gray matter, and upregulation of proinflammatory mediators (e.g., cytokines) by reactivation of astrocytes and microglial cells are the main functional, structural, and molecular neuroplasticity changes observed in the above supraspinal structures, associated with pathological pain. Studying these changes in greater depth may lead to the implementation and improvement of new therapeutic strategies against pathological pain. Anat Rec, 300:1481-1501, 2017. © 2017 Wiley Periodicals, Inc.

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“…However, under mGluR stimulation, A-kinase anchoring protein (AKAP) binds to PKC and reduces the accessibility of the PKC kinase site, resulting in a decrease in M current ( Delmas and Brown, 2005 ; Kreir et al, 2019 ). In hippocampal and anterior cingulate cortex neurons, an increase in PLC–PKC activity via the mGluR signaling pathway also reduces HCN1 channel expression and HCN currents ( Williams et al, 2015 ; Gao et al, 2016 ). Additionally, other signaling pathways that affect the above mentioned protein kinases can modulate the mAHP channels and regulate synaptic and cellular functions.…”

Section: Endogenous Regulators Of the Mahp Channel Activitymentioning

confidence: 99%

Physiology and Therapeutic Potential of SK, H, and M Medium AfterHyperPolarization Ion Channels

Dwivedi

Bhalla

2021

Front. Mol. Neurosci.

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SK, HCN, and M channels are medium afterhyperpolarization (mAHP)-mediating ion channels. The three channels co-express in various brain regions, and their collective action strongly influences cellular excitability. However, significant diversity exists in the expression of channel isoforms in distinct brain regions and various subcellular compartments, which contributes to an equally diverse set of specific neuronal functions. The current review emphasizes the collective behavior of the three classes of mAHP channels and discusses how these channels function together although they play specialized roles. We discuss the biophysical properties of these channels, signaling pathways that influence the activity of the three mAHP channels, various chemical modulators that alter channel activity and their therapeutic potential in treating various neurological anomalies. Additionally, we discuss the role of mAHP channels in the pathophysiology of various neurological diseases and how their modulation can alleviate some of the symptoms.

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Activation of mGluR1 contributes to neuronal hyperexcitability in the rat anterior cingulate cortex via inhibition of HCN channels

Cited by 31 publications

References 81 publications

The brain-penetrant 5-HT 7 receptor agonist LP-211 reduces the sensory and affective components of neuropathic pain

The brain-penetrant 5-HT 7 receptor agonist LP-211 reduces the sensory and affective components of neuropathic pain

Neuroplasticity of Supraspinal Structures Associated with Pathological Pain

Physiology and Therapeutic Potential of SK, H, and M Medium AfterHyperPolarization Ion Channels

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