Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn

Boyce, Susan; Wyatt, A. C.; Webb, J.K.; O’Donnell, Ruth; Mason, G.S.; Rigby, Michael; Sirinathsinghji, D.; Hill, Ray; Rupniak, N. M. J.

doi:10.1016/s0028-3908(98)00218-4

Cited by 323 publications

(246 citation statements)

References 35 publications

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“…There is an increasingly bolstered association between pain (including chronic varieties) and central glutamatergic dysfunction, such that NMDA antagonists, and more specifically NR2B antagonists, are being studied for its treatment; NR2B antagonists are antinociceptive at doses below those that impair motor coordination. 184 Additionally, studies have shown that group I metabotropic receptors are involved in the development and maintenance of pronociceptive hypersensitivity, and group I receptor antagonists are antinociceptive, as are agonists for group II receptors, in keeping with their respective effects on anxiety (see Chizh 185 for a recent review). We include these final points within the Future Directions section as an impetus to merge different fields of existing research to develop studies to address common neurobiological mechanisms of illness behavior.…”

Section: Future Directionsmentioning

confidence: 99%

Advances in the treatment of anxiety: Targeting glutamate

Simon

Gorman

2006

NeuroRX

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Our current psychopharmacological treatments for anxiety disorders evince a number of shortcomings, including troublesome side effects and lack of primary effects. Whereas many new drugs have been developed in the past few decades, most are based on outmoded theories of the pathogenesis of these disorders (i.e., monoamine hypotheses), thus frustrating our ability to create more specific and effective interventions. Recently, however, the neurobiological literature has shown a convergence of findings focusing on the glutamatergic system in anxiety disorders, and the growth of pharmacological tools targeting these receptors has led to the development of novel treatments having anxiolytic effects in humans and animals alike. Additionally, as this system is showing promise as a final common pathway in the pathogenesis of anxiety disorders, we may be able to employ glutamate-specific neuroimaging techniques (e.g., N-acetyl-aspartate, GLX) to both guide treatment decisions and present reliable objective biomarkers for treatment efficacy.

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Section: Future Directionsmentioning

confidence: 99%

Advances in the treatment of anxiety: Targeting glutamate

Simon

Gorman

2006

NeuroRX

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“…Although, this type of compounds was initially thought to interact with the polyamine site, recent experiments using chimeric NR2A/NR2B subunits revealed that the major determinant of the inhibitory effect of ifenprodil -the initial chemical lead of the NR2B subunit selective antagonists -localizes to a distinct site of the NR2B subunit [66,34]. The NR2B subunit selective antagonists showed potency in animal models of neurodegeneration [99], Parkinson disease [155,156,200,220], and hyperalgesia [19,29,36,57]. It was also realized that this type of compounds lacks the serious side effects of the classic NMDAR antagonists' [162].…”

Section: Nr2b Subunit Selective Nmdar Antagonistsmentioning

confidence: 99%

“…Although, like other un-competitive NMDAR antagonists they may have some adverse effect on learning and memory, it was proved that they have a wider separation between doses that are effective in seizure or stroke models and those that disrupt learning and memory. The limited information on the novel NR2B subunit selective antagonists (Table 1) such as CP-101,606 (traxoprodil) [33,98], Ro25-6981 [59], Co-101244 [225], CI-1041 [35] and RG-1103 [18] also suggests that these drugs are better tolerated and are largely devoid of adverse CNS effects at antinociceptive doses, at least with respect to psychotomimetic, ataxic and sedative effects [19,29,35,57,146,203].…”

Section: Nr2b Subunit Selective Nmdar Antagonistsmentioning

confidence: 99%

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

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Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "upregulation" of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal.Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms,but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence.

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“…The possibility that the GluN2B subunit has a special role in the low and high threshold polysynaptic pathways to NK1Rϩ neurons is suggested by observations that GluN2B-specific antagonists are able to alleviate allodynia and hyperalgesia. Intrathecal administration of GluN2B antagonists blocks or decreases certain forms of chronic pain including carrageenan-induced mechanical hyperalgesia (Taniguchi et al, 1997) and nerve injury-induced mechanical allodynia (Boyce et al, 1999;Chizh et al, 2001a). Here we use whole-cell patch-clamp recording, fluorescence imaging, and receptor pharmacology to investigate the identity of synaptic NMDA receptors expressed at primary afferent synapses onto lamina I dorsal horn neurons and in polysynaptic pathways revealed by disinhibition.…”

Section: Introductionmentioning

confidence: 99%

Synaptic GluN2A and GluN2B Containing NMDA Receptors within the Superficial Dorsal Horn Activated following Primary Afferent Stimulation

Tong¹,

MacDermott

2014

Journal of Neuroscience

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NMDA receptors are important elements in pain signaling in the spinal cord dorsal horn. They are heterotetramers, typically composed of two GluN1 and two of four GluN2 subunits: GluN2A-2D. Mice lacking some of the GluN2 subunits show deficits in pain transmission yet functional synaptic localization of these receptor subtypes in the dorsal horn has not been fully resolved. In this study, we have investigated the composition of synaptic NMDA receptors expressed in monosynaptic and polysynaptic pathways from peripheral sensory fibers to lamina I neurons in rats. We focused on substance P receptor-expressing (NK1Rϩ) projection neurons, critical for expression of hyperalgesia and allodynia. EAB-318 and (R)-CPP, GluN2A/B antagonists, blocked both monosynaptic and polysynaptic NMDA EPSCs initiated by primary afferent activation by ϳ90%. Physiological measurements exploiting the voltage dependence of monosynaptic EPSCs similarly indicated dominant expression of GluN2A/B types of synaptic NMDA receptors. In addition, at synapses between C fibers and NK1Rϩ neurons, NMDA receptor activation initiated a secondary, depolarizing current. Ifenprodil, a GluN2B antagonist, caused modest suppression of monosynaptic NMDA EPSC amplitudes, but had a widely variable, sometimes powerful, effect on polysynaptic responses following primary afferent stimulation when inhibitory inputs were blocked to mimic neuropathic pain. We conclude that GluN2B subunits are moderately expressed at primary afferent synapses on lamina I NK1Rϩ neurons, but play more important roles for polysynaptic NMDA EPSCs driven by primary afferents following disinhibition, supporting the view that the analgesic effect of the GluN2B antagonist on neuropathic pain is at least in part, within the spinal cord.

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Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn

Cited by 323 publications

References 35 publications

Advances in the treatment of anxiety: Targeting glutamate

Advances in the treatment of anxiety: Targeting glutamate

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Synaptic GluN2A and GluN2B Containing NMDA Receptors within the Superficial Dorsal Horn Activated following Primary Afferent Stimulation

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