The Experts below are selected from a list of 213 Experts worldwide ranked by ideXlab platform
Kristopher T. Kahle - One of the best experts on this subject based on the ideXlab platform.
-
Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition
Science Signaling, 2016Co-Authors: Kristopher T. Kahle, Takao Omura, Jean Francois Schmouth, Janet Laganiere, Daniel Rochefort, Valérie Lavastre, Alban Latremoliere, Jinwei Zhang, Nick Andrews, Pascale HinceAbstract:HSN2 is a nervous system predominant exon of the gene encoding the kinase WNK1 and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. The HSN2-containing splice variant is referred to as WNK1/HSN2. We created a knockout mouse specifically lacking the Hsn2 exon of Wnk1 . Although these mice had normal Spinal Neuron and peripheral sensory Neuron morphology and distribution, the mice were less susceptible to hypersensitivity to cold and mechanical stimuli after peripheral nerve injury. In contrast, thermal and mechanical nociceptive responses were similar to control mice in an inflammation-induced pain model. In the nerve injury model of neuropathic pain, WNK1/HSN2 contributed to a maladaptive decrease in the activity of the K + -Cl − cotransporter KCC2 by increasing its inhibitory phosphorylation at Thr 906 and Thr 1007 , resulting in an associated loss of GABA (γ-aminobutyric acid)–mediated inhibition of Spinal pain-transmitting nerves. Electrophysiological analysis showed that WNK1/HSN2 shifted the concentration of Cl − such that GABA signaling resulted in a less hyperpolarized state (increased Neuronal activity) rather than a more hyperpolarized state (decreased Neuronal activity) in mouse Spinal nerves. Pharmacologically antagonizing WNK activity reduced cold allodynia and mechanical hyperalgesia, decreased KCC2 Thr 906 and Thr 1007 phosphorylation, and restored GABA-mediated inhibition (hyperpolarization) of injured Spinal cord lamina II Neurons. These data provide mechanistic insight into, and a compelling therapeutic target for treating, neuropathic pain after nerve injury.
-
inhibition of the kinase wnk1 hsn2 ameliorates neuropathic pain by restoring gaba inhibition
Science Signaling, 2016Co-Authors: Jean Francois Schmouth, Valérie Lavastre, Alban Latremoliere, Kristopher T. Kahle, Jinwei Zhang, Nick Andrews, Takao OmuraAbstract:HSN2 is a nervous system predominant exon of the gene encoding the kinase WNK1 and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. The HSN2-containing splice variant is referred to as WNK1/HSN2. We created a knockout mouse specifically lacking the Hsn2 exon of Wnk1 . Although these mice had normal Spinal Neuron and peripheral sensory Neuron morphology and distribution, the mice were less susceptible to hypersensitivity to cold and mechanical stimuli after peripheral nerve injury. In contrast, thermal and mechanical nociceptive responses were similar to control mice in an inflammation-induced pain model. In the nerve injury model of neuropathic pain, WNK1/HSN2 contributed to a maladaptive decrease in the activity of the K + -Cl − cotransporter KCC2 by increasing its inhibitory phosphorylation at Thr 906 and Thr 1007 , resulting in an associated loss of GABA (γ-aminobutyric acid)–mediated inhibition of Spinal pain-transmitting nerves. Electrophysiological analysis showed that WNK1/HSN2 shifted the concentration of Cl − such that GABA signaling resulted in a less hyperpolarized state (increased Neuronal activity) rather than a more hyperpolarized state (decreased Neuronal activity) in mouse Spinal nerves. Pharmacologically antagonizing WNK activity reduced cold allodynia and mechanical hyperalgesia, decreased KCC2 Thr 906 and Thr 1007 phosphorylation, and restored GABA-mediated inhibition (hyperpolarization) of injured Spinal cord lamina II Neurons. These data provide mechanistic insight into, and a compelling therapeutic target for treating, neuropathic pain after nerve injury.
Takao Omura - One of the best experts on this subject based on the ideXlab platform.
-
Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition
Science Signaling, 2016Co-Authors: Kristopher T. Kahle, Takao Omura, Jean Francois Schmouth, Janet Laganiere, Daniel Rochefort, Valérie Lavastre, Alban Latremoliere, Jinwei Zhang, Nick Andrews, Pascale HinceAbstract:HSN2 is a nervous system predominant exon of the gene encoding the kinase WNK1 and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. The HSN2-containing splice variant is referred to as WNK1/HSN2. We created a knockout mouse specifically lacking the Hsn2 exon of Wnk1 . Although these mice had normal Spinal Neuron and peripheral sensory Neuron morphology and distribution, the mice were less susceptible to hypersensitivity to cold and mechanical stimuli after peripheral nerve injury. In contrast, thermal and mechanical nociceptive responses were similar to control mice in an inflammation-induced pain model. In the nerve injury model of neuropathic pain, WNK1/HSN2 contributed to a maladaptive decrease in the activity of the K + -Cl − cotransporter KCC2 by increasing its inhibitory phosphorylation at Thr 906 and Thr 1007 , resulting in an associated loss of GABA (γ-aminobutyric acid)–mediated inhibition of Spinal pain-transmitting nerves. Electrophysiological analysis showed that WNK1/HSN2 shifted the concentration of Cl − such that GABA signaling resulted in a less hyperpolarized state (increased Neuronal activity) rather than a more hyperpolarized state (decreased Neuronal activity) in mouse Spinal nerves. Pharmacologically antagonizing WNK activity reduced cold allodynia and mechanical hyperalgesia, decreased KCC2 Thr 906 and Thr 1007 phosphorylation, and restored GABA-mediated inhibition (hyperpolarization) of injured Spinal cord lamina II Neurons. These data provide mechanistic insight into, and a compelling therapeutic target for treating, neuropathic pain after nerve injury.
-
inhibition of the kinase wnk1 hsn2 ameliorates neuropathic pain by restoring gaba inhibition
Science Signaling, 2016Co-Authors: Jean Francois Schmouth, Valérie Lavastre, Alban Latremoliere, Kristopher T. Kahle, Jinwei Zhang, Nick Andrews, Takao OmuraAbstract:HSN2 is a nervous system predominant exon of the gene encoding the kinase WNK1 and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. The HSN2-containing splice variant is referred to as WNK1/HSN2. We created a knockout mouse specifically lacking the Hsn2 exon of Wnk1 . Although these mice had normal Spinal Neuron and peripheral sensory Neuron morphology and distribution, the mice were less susceptible to hypersensitivity to cold and mechanical stimuli after peripheral nerve injury. In contrast, thermal and mechanical nociceptive responses were similar to control mice in an inflammation-induced pain model. In the nerve injury model of neuropathic pain, WNK1/HSN2 contributed to a maladaptive decrease in the activity of the K + -Cl − cotransporter KCC2 by increasing its inhibitory phosphorylation at Thr 906 and Thr 1007 , resulting in an associated loss of GABA (γ-aminobutyric acid)–mediated inhibition of Spinal pain-transmitting nerves. Electrophysiological analysis showed that WNK1/HSN2 shifted the concentration of Cl − such that GABA signaling resulted in a less hyperpolarized state (increased Neuronal activity) rather than a more hyperpolarized state (decreased Neuronal activity) in mouse Spinal nerves. Pharmacologically antagonizing WNK activity reduced cold allodynia and mechanical hyperalgesia, decreased KCC2 Thr 906 and Thr 1007 phosphorylation, and restored GABA-mediated inhibition (hyperpolarization) of injured Spinal cord lamina II Neurons. These data provide mechanistic insight into, and a compelling therapeutic target for treating, neuropathic pain after nerve injury.
Valérie Lavastre - One of the best experts on this subject based on the ideXlab platform.
-
Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition
Science Signaling, 2016Co-Authors: Kristopher T. Kahle, Takao Omura, Jean Francois Schmouth, Janet Laganiere, Daniel Rochefort, Valérie Lavastre, Alban Latremoliere, Jinwei Zhang, Nick Andrews, Pascale HinceAbstract:HSN2 is a nervous system predominant exon of the gene encoding the kinase WNK1 and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. The HSN2-containing splice variant is referred to as WNK1/HSN2. We created a knockout mouse specifically lacking the Hsn2 exon of Wnk1 . Although these mice had normal Spinal Neuron and peripheral sensory Neuron morphology and distribution, the mice were less susceptible to hypersensitivity to cold and mechanical stimuli after peripheral nerve injury. In contrast, thermal and mechanical nociceptive responses were similar to control mice in an inflammation-induced pain model. In the nerve injury model of neuropathic pain, WNK1/HSN2 contributed to a maladaptive decrease in the activity of the K + -Cl − cotransporter KCC2 by increasing its inhibitory phosphorylation at Thr 906 and Thr 1007 , resulting in an associated loss of GABA (γ-aminobutyric acid)–mediated inhibition of Spinal pain-transmitting nerves. Electrophysiological analysis showed that WNK1/HSN2 shifted the concentration of Cl − such that GABA signaling resulted in a less hyperpolarized state (increased Neuronal activity) rather than a more hyperpolarized state (decreased Neuronal activity) in mouse Spinal nerves. Pharmacologically antagonizing WNK activity reduced cold allodynia and mechanical hyperalgesia, decreased KCC2 Thr 906 and Thr 1007 phosphorylation, and restored GABA-mediated inhibition (hyperpolarization) of injured Spinal cord lamina II Neurons. These data provide mechanistic insight into, and a compelling therapeutic target for treating, neuropathic pain after nerve injury.
-
inhibition of the kinase wnk1 hsn2 ameliorates neuropathic pain by restoring gaba inhibition
Science Signaling, 2016Co-Authors: Jean Francois Schmouth, Valérie Lavastre, Alban Latremoliere, Kristopher T. Kahle, Jinwei Zhang, Nick Andrews, Takao OmuraAbstract:HSN2 is a nervous system predominant exon of the gene encoding the kinase WNK1 and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. The HSN2-containing splice variant is referred to as WNK1/HSN2. We created a knockout mouse specifically lacking the Hsn2 exon of Wnk1 . Although these mice had normal Spinal Neuron and peripheral sensory Neuron morphology and distribution, the mice were less susceptible to hypersensitivity to cold and mechanical stimuli after peripheral nerve injury. In contrast, thermal and mechanical nociceptive responses were similar to control mice in an inflammation-induced pain model. In the nerve injury model of neuropathic pain, WNK1/HSN2 contributed to a maladaptive decrease in the activity of the K + -Cl − cotransporter KCC2 by increasing its inhibitory phosphorylation at Thr 906 and Thr 1007 , resulting in an associated loss of GABA (γ-aminobutyric acid)–mediated inhibition of Spinal pain-transmitting nerves. Electrophysiological analysis showed that WNK1/HSN2 shifted the concentration of Cl − such that GABA signaling resulted in a less hyperpolarized state (increased Neuronal activity) rather than a more hyperpolarized state (decreased Neuronal activity) in mouse Spinal nerves. Pharmacologically antagonizing WNK activity reduced cold allodynia and mechanical hyperalgesia, decreased KCC2 Thr 906 and Thr 1007 phosphorylation, and restored GABA-mediated inhibition (hyperpolarization) of injured Spinal cord lamina II Neurons. These data provide mechanistic insight into, and a compelling therapeutic target for treating, neuropathic pain after nerve injury.
Jean Francois Schmouth - One of the best experts on this subject based on the ideXlab platform.
-
Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition
Science Signaling, 2016Co-Authors: Kristopher T. Kahle, Takao Omura, Jean Francois Schmouth, Janet Laganiere, Daniel Rochefort, Valérie Lavastre, Alban Latremoliere, Jinwei Zhang, Nick Andrews, Pascale HinceAbstract:HSN2 is a nervous system predominant exon of the gene encoding the kinase WNK1 and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. The HSN2-containing splice variant is referred to as WNK1/HSN2. We created a knockout mouse specifically lacking the Hsn2 exon of Wnk1 . Although these mice had normal Spinal Neuron and peripheral sensory Neuron morphology and distribution, the mice were less susceptible to hypersensitivity to cold and mechanical stimuli after peripheral nerve injury. In contrast, thermal and mechanical nociceptive responses were similar to control mice in an inflammation-induced pain model. In the nerve injury model of neuropathic pain, WNK1/HSN2 contributed to a maladaptive decrease in the activity of the K + -Cl − cotransporter KCC2 by increasing its inhibitory phosphorylation at Thr 906 and Thr 1007 , resulting in an associated loss of GABA (γ-aminobutyric acid)–mediated inhibition of Spinal pain-transmitting nerves. Electrophysiological analysis showed that WNK1/HSN2 shifted the concentration of Cl − such that GABA signaling resulted in a less hyperpolarized state (increased Neuronal activity) rather than a more hyperpolarized state (decreased Neuronal activity) in mouse Spinal nerves. Pharmacologically antagonizing WNK activity reduced cold allodynia and mechanical hyperalgesia, decreased KCC2 Thr 906 and Thr 1007 phosphorylation, and restored GABA-mediated inhibition (hyperpolarization) of injured Spinal cord lamina II Neurons. These data provide mechanistic insight into, and a compelling therapeutic target for treating, neuropathic pain after nerve injury.
-
inhibition of the kinase wnk1 hsn2 ameliorates neuropathic pain by restoring gaba inhibition
Science Signaling, 2016Co-Authors: Jean Francois Schmouth, Valérie Lavastre, Alban Latremoliere, Kristopher T. Kahle, Jinwei Zhang, Nick Andrews, Takao OmuraAbstract:HSN2 is a nervous system predominant exon of the gene encoding the kinase WNK1 and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. The HSN2-containing splice variant is referred to as WNK1/HSN2. We created a knockout mouse specifically lacking the Hsn2 exon of Wnk1 . Although these mice had normal Spinal Neuron and peripheral sensory Neuron morphology and distribution, the mice were less susceptible to hypersensitivity to cold and mechanical stimuli after peripheral nerve injury. In contrast, thermal and mechanical nociceptive responses were similar to control mice in an inflammation-induced pain model. In the nerve injury model of neuropathic pain, WNK1/HSN2 contributed to a maladaptive decrease in the activity of the K + -Cl − cotransporter KCC2 by increasing its inhibitory phosphorylation at Thr 906 and Thr 1007 , resulting in an associated loss of GABA (γ-aminobutyric acid)–mediated inhibition of Spinal pain-transmitting nerves. Electrophysiological analysis showed that WNK1/HSN2 shifted the concentration of Cl − such that GABA signaling resulted in a less hyperpolarized state (increased Neuronal activity) rather than a more hyperpolarized state (decreased Neuronal activity) in mouse Spinal nerves. Pharmacologically antagonizing WNK activity reduced cold allodynia and mechanical hyperalgesia, decreased KCC2 Thr 906 and Thr 1007 phosphorylation, and restored GABA-mediated inhibition (hyperpolarization) of injured Spinal cord lamina II Neurons. These data provide mechanistic insight into, and a compelling therapeutic target for treating, neuropathic pain after nerve injury.
Horacio Vanegas - One of the best experts on this subject based on the ideXlab platform.
-
activity correlations between on like and off like cells of the rostral ventromedial medulla and simultaneously recorded wide dynamic range Neurons of the Spinal dorsal horn in rats
Brain Research, 2016Co-Authors: Rafael Salas, Karla Ramirez, Horacio Vanegas, Enrique VazquezAbstract:Considerable evidence supports the notion that on- and off-cells of the rostral ventromedial medulla (RVM) facilitate and depress, respectively, Spinal nociceptive transmission. This notion stems from a covariation of on- or off-cell activities and Spinal nocifensive reflexes. Such covariation could theoretically be due to their independently responding to a common source, or to an RVM-derived modulation of ventral horn Neurons. Here, we tested whether on- and off-cells indeed modulate Spinal nociceptive Neurons. In deeply anesthetized rats, unitary recordings were simultaneously made from an RVM on-like or off-like cell and a Spinal nociceptive Neuron that shared a receptive field (RF) at a hind paw. Action potential firing in RVM/Spinal Neuron pairs was highly correlated, positively for on-like cells and negatively for off-like cells, both during ongoing activity and during application of calibrated noxious pressure to the RF. Microinjection of morphine into RVM induced a correlated decrease in on-like cell/Spinal Neuron ongoing activity and response to noxious stimulation. RVM morphine induced changes in off-like cell activity that were not correlated with Spinal Neuronal activity. These results suggest that on-cells exert a positive modulation upon Spinal nociceptive Neurons, upstream to ventral horn circuits and plausibly at the origin of nociceptive information that eventually reaches the cerebral cortex. On-cells may in this manner contribute to inflammation- and neuropathy-induced increases in withdrawal reflexes. Most significantly, on-cell modulation of nociceptive Neurons may be a key factor in clinical pain conditions such as hyperalgesia and allodynia.
-
encoding of noxious stimulus intensity by putative pain modulating Neurons in the rostral ventromedial medulla and by simultaneously recorded nociceptive Neurons in the Spinal dorsal horn of rats
Pain, 2001Co-Authors: Norma Edenia Batista Hernandez, Horacio VanegasAbstract:Abstract Neurons in the nucleus raphe magnus and adjacent structures of the rostral ventromedial medulla (RVM) are involved in the control of nociceptive transmission. In the RVM the so-called on-cells are excited, and the so-called off-cells are inhibited, by noxious stimuli applied almost anywhere on the body surface, thus showing that they receive information from Spinal and trigeminal nociceptive Neurons. In deeply anesthetized rats, recordings were made from RVM Neurons that resembled on- and off-cells (herein called putative on- and off-cells) in order to investigate (1) how they encode the intensity of thermal noxious stimuli (46–56°C) applied to a hindpaw, and (2) how their encoding properties relate to those of simultaneously recorded Spinal Neurons. In 49 of 98 cases, a graded increase in the stimulus temperature caused a monotonic decrease in the response latency of putative on-cells, putative off-cells and Spinal Neurons, while the response discharge rate monotonically increased for putative on-cells and Spinal Neurons and decreased for putative off-cells. In the majority of simultaneous recordings of RVM and Spinal Neurons, the latency and discharge rate of the putative on- or off-cell were highly correlated with the latency and discharge rate of the Spinal Neuron, and the stimulus/response slopes were similar. These results show that putative on- and off-cells can encode the stimulus intensity in terms of response latency and discharge rate, and suggest that such encoding closely reflects Spinal Neuronal encoding. This may be relevant for the transmission and modulation of pain information by RVM Neurons.