Glutamate-induced currents reveal three functionally distinct NMDA receptor populations in rat dorsal horn – effects of peripheral nerve lesion and inflammation

Karlsson, Urban; Sjödin, Johanna; Möller, Kristina Ängeby; Johansson, Staffan; Wikström, Lilian; Näsström, Jacques

doi:10.1016/s0306-4522(02)00140-9

Cited by 43 publications

(32 citation statements)

References 30 publications

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“…In another study, formalin injected into the paw increased NR2A mRNA expression in the spinal cord (Gaunitz et al, 2002). However, up-regulation of NR2A mRNA might be specific for inflammatory pain states since nerve injury decreased NR2A in the spinal cord (Karlsson et al, 2002). Taken together, the current study indicates that NR2B selectivity is not the only avenue for improving the adverse effect profile of NMDA antagonists; selectivity for other NMDA receptor subunits might also be important for identifying compounds with therapeutic potential.…”

Section: Discussionmentioning

confidence: 62%

Effects of the N-Methyl-d-aspartate Receptor Antagonist Perzinfotel [EAA-090; [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic Acid] on Chemically Induced Thermal Hypersensitivity

Brandt

Cummons²,

Potestio³

et al. 2005

J Pharmacol Exp Ther

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Effects of the N-Methyl-D-aspartate Receptor AntagonistPerzinfotel [2][3][4][5][6][7][8] ABSTRACT Perzinfotel [2][3][4][5][6][7][8].0]non-1(7)-en-2-yl)-ethyl]phosphonic acid] is a selective, competitive Nmethyl-D-aspartate (NMDA) receptor antagonist with high affinity for the glutamate site. The current study evaluated whether perzinfotel would have antinociceptive effects or block thermal hypersensitivity associated with the administration of chemical irritants in rats. Perzinfotel lacked antinociceptive effects but dose-and time-dependently blocked prostaglandin E 2 (PGE 2 )-and capsaicin-induced thermal hypersensitivity in a warm-water tail-withdrawal assay in rats. Doses of 10 mg/kg intraperitoneal or 100 mg/kg oral blocked PGE 2 -induced hypersensitivity by 60 to 80%. The magnitude of reversal was greater than other negative modulators of the NMDA receptor studied, such as uncompetitive channel blockers (e.g., memantine, dizocilpine, and ketamine), a NR2B selective antagonist (e.g., ifenprodil), and other glutamate antagonists [e.g., selfotel, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), D,L-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid (CGP-39653)], up to doses that suppressed operant rates of responding. In contrast to other negative modulators of the NMDA receptor studied, which typically decreased operant rates of responding at doses that lacked antinociceptive effects, perzinfotel did not modify response rates at doses that blocked irritant-induced thermal hypersensitivity. Collectively, these studies demonstrate that perzinfotel has therapeutic ratios for effectiveness versus adverse effects superior to those seen with other competitive and uncompetitive NMDA receptor antagonists studied.Excitatory amino acids acting at NMDA receptors play a role in both acute and chronic pain. Increases in afferent input and glutamate release within the spinal cord have been observed after peripheral injection of an irritant (e.g., carrageenan) or tissue injury (Sluka and Westlund, 1993;Kawamata and Omote, 1996;Dickenson et al., 1997). Repeated stimulation of primary afferent fibers can progressively increase the magnitude and duration of action potentials in spinal cord (often termed "windup"), which can lead to central sensitization (Ma and Woolf, 1995). This neuronal hyperexcitability manifests itself in a lowered threshold to evoked activity (i.e., hyperalgesia), an expansion of receptive fields (i.e., secondary hypersensitivity), and an ability of non-noxious input to evoke neuronal activity (i.e., allodynia). In preclinical studies, NMDA receptor antagonists reverse neuronal hyperexcitability and reverse hypersensitivity in several inflammatory and neuropathic animal pain models associated with various pathophysiologic mechanisms (Mao et al., 1993;Chaplan et al., 1997;Suzuki et al., 2001). In clinical studies, NMDA receptor antagonists, such as ketamine and dextromethorphan, reduce windup pain, spontaneous pain, hyperalgesia, and allodynia in patients with postherpetic neuralgia pain, phantom ...

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Section: Discussionmentioning

confidence: 62%

Effects of the N-Methyl-d-aspartate Receptor Antagonist Perzinfotel [EAA-090; [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic Acid] on Chemically Induced Thermal Hypersensitivity

Brandt

Cummons²,

Potestio³

et al. 2005

J Pharmacol Exp Ther

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“…62 The central sensitization that occurs in the spinal dorsal horn is widely held to be an important event in the pathway leading to neuropathic pain. In a rat neuropathic pain model of L5 spinal nerve transection, there was reduced expression of NR2A, 15 whereas in a model of partial chronic constriction injury to the sciatic nerve there was increased expression of NR2B (but not NR2A) and reduced NR1 in the superficial dorsal horn. 63 In animal neuropathic pain models, NMDA receptor channel blockers such as memantine, MK801, and ketamine attenuate thermal and mechanical hyperalgesia in rats.…”

Section: Function In Chronic Painmentioning

confidence: 91%

“…All NMDA receptor subunits (NR1 and NR2A-D) are expressed in the spinal dorsal horn; however, NR2B exhibits the largest expression among NR2 subunits, followed by decreasing proportions of NR2C, NR2A, and NR2D. 15 NR2A was found to be present in all parts of the gray matter except lamina II, but NR2B was largely restricted to lamina II. 16 Other studies also showed that the NR2B subunit has a restricted distribution in the superficial dorsal horn.…”

Section: Synaptic Plasticity In the Brainmentioning

confidence: 93%

Targeting the NMDA Receptor Subunit NR2B for the Treatment of Neuropathic Pain

2009

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Summary:Neuropathic pain is generally defined as a chronic pain state resulting from peripheral or central nerve injury, or both. An effective treatment for neuropathic pain is still lacking. The NMDA receptor, one type of the ionotropic glutamate receptors, is known to be important for triggering long-lasting changes in synapses. NMDA receptor-dependent synaptic plasticity plays roles not only in physiological functions such as learning and memory, but also in unwanted pathological conditions such as chronic pain. This review addresses recent progress on NMDA receptors in neuropathic pain, with particular emphasis on the NR2B-subunitcontaining receptors. The expression and function of NMDA receptors in synaptic plasticity in the pain transmission pathway from dorsal root ganglia to the anterior cingulate cortex is reviewed, and preclinical and clinical investigations of selective NMDA receptor in neuropathic pain are discussed. The NMDA receptors, in particular NR2B-containing NMDA receptors, serve as promising targets for treatment of neuropathic pain.

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“…Although the NR1 subunit is a glycine binding site and universally expressed in all NMDAR, the NR2 is the glutamate-binding subunit and is the major molecular determinants of the functional diversity. More recently, functional expression of NR2B-containing NMDAR have been predominantly been found on the soma of dorsal root ganglia, suggesting that NR2B subunits are of particular importance for pain perception (28).Previous studies indicate that the NMDAR subunit composition vary not only with the type of insult but also with the duration of injury and inflammation (3,4,23). The differential expression of the NR1 component both developmentally and regionally affects many aspects of the channel's function such as ligand binding, membrane expression, phosphorylation, and downstream signaling (7).…”

mentioning

confidence: 99%

“…Previous studies indicate that the NMDAR subunit composition vary not only with the type of insult but also with the duration of injury and inflammation (3,4,23). The differential expression of the NR1 component both developmentally and regionally affects many aspects of the channel's function such as ligand binding, membrane expression, phosphorylation, and downstream signaling (7).…”

mentioning

confidence: 99%

Alterations in N-methyl-d-aspartate receptor subunits in primary sensory neurons following acid-induced esophagitis in cats

Banerjee

Medda²,

Zheng³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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The objective of this study was to use a cat model of gastroesophageal reflux disease (GERD) to investigate the expression of the NR1 and NR2A subunits of NMDAR in the vagal and spinal afferent fibers innervating the esophagus. Two groups of cats (Acid-7D and PBS-7D) received 0.1 N HCl (pH 1.2) or 0.1 M PBS (pH 7.4) infusion in the esophagus (1 ml/min for 30 min/day for 7 days), respectively. NR1 splice variants (both NH 2 and COOH terminals) and NR2A in the thoracic dorsal root ganglia (DRGs), nodose ganglia (NGs), and esophagus were evaluated by RT-PCR, Western blot, and immunohistochemistry. Acid produced marked inflammation and a significant increase in eosinophil peroxidase and myeloperoxidase contents compared with PBS-infused esophagus. The NR1-4 splice variant gene exhibited a significant upregulation in DRGs and esophagus after acid infusion. In DRGs, NGs, and esophagus, acid infusion resulted in significant upregulation of NR1 and downregulation of NR2A subunit gene expression. A significant increase in NR1 polypeptide expression was observed in DRGs and NGs from Acid-7D compared with control. In conclusion, long-term acid infusion in the cat esophagus resulted in ulcerative esophagitis and differential expressions of NR1 and NR2A subunits. It is possible that these changes may in part contribute to esophageal hypersensitivity observed in reflux esophagitis.esophagus; dorsal root ganglia; nodose ganglia; esophagitis; NMDA receptor subunit NEURONAL SENSITIZATION IS an important underlying mechanism that can result in visceral hypersensitivity. For example, acid exposure alters primary sensory neurons innervating the gut and results in enhanced responsiveness of spinal neurons and gastrointestinal hypersensitivity (19,22). Several molecular targets have been proposed as key players in the induction and maintenance of central and peripheral sensitization including the N-methyl-D-aspartate receptors (NMDAR), transient receptor potential vanilloid 1, acid-sensing ion channels, and TTXresistant Na channels (1, 2, 5a, 16, 17, 20, 29). The NMDAR, in particular, are believed to be involved in synaptic transmission between primary afferents and dorsal horn neurons (16,34), in addition to their participation in central sensitization in spinal neurons. These receptors have not only been shown to be present in the peripheral terminals of visceral primary afferents supplying the gastrointestinal tract and other hollow viscera, but their involvement in release of specific neurotransmitters during pain transmission at both the peripheral and central terminals of the sensory neurons has also been clearly documented (30).The NMDAR are ligand-gated ion channels that have an important role in both the transduction of noxious mechanical stimuli as well as in the development of central sensitization. These receptors have been shown to contribute to colonic inflammation-evoked hyperalgesia and dorsal horn neuron hyperexcitability (25, 37). "Wind-up" of spinal neurons to somatic nociceptive stimuli and long-term potentiation ...

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Glutamate-induced currents reveal three functionally distinct NMDA receptor populations in rat dorsal horn – effects of peripheral nerve lesion and inflammation

Cited by 43 publications

References 30 publications

Effects of the N-Methyl-d-aspartate Receptor Antagonist Perzinfotel [EAA-090; [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic Acid] on Chemically Induced Thermal Hypersensitivity

Effects of the N-Methyl-d-aspartate Receptor Antagonist Perzinfotel [EAA-090; [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic Acid] on Chemically Induced Thermal Hypersensitivity

Targeting the NMDA Receptor Subunit NR2B for the Treatment of Neuropathic Pain

Alterations in N-methyl-d-aspartate receptor subunits in primary sensory neurons following acid-induced esophagitis in cats

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