Antinociceptive activity of CP‐101,606, an NMDA receptor NR2B subunit antagonist

Taniguchi, Kana; Shinjo, Keiko; Mizutani, Masami; Shimada, Kaoru; Ishikawa, Toshihisa; Menniti, Frank S.; Nagahisa, Atsushi

doi:10.1038/sj.bjp.0701445

Cited by 127 publications

(63 citation statements)

References 7 publications

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“…CHF3381 potently and dose dependently inhibited carrageenan-induced thermal and mechanical hyperalgesia, in agreement with studies indicating a contribution of the NMDA receptor in this model (Ren et al, 1992;Taniguchi et al, 1997). CHF3381 did not modify the physiological responses of the uninjured paw to thermal and mechanical stimuli at the doses tested.…”

Section: Discussionsupporting

confidence: 74%

Antinociceptive Activity of the N-Methyl-d-aspartate Receptor Antagonist N-(2-Indanyl)-glycinamide Hydrochloride (CHF3381) in Experimental Models of Inflammatory and Neuropathic Pain

Villetti¹,

Bergamaschi²,

Bassani³

et al. 2003

J Pharmacol Exp Ther

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N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) is a novel low-affinity, noncompetitive N-methyl-D-aspartate receptor antagonist. The current study compared the antinociceptive effects of CHF3381 with those of gabapentin and memantine in in vitro and in vivo models of pain. In isolated rat spinal cord, CHF3381 and memantine, but not gabapentin, produced similar inhibition of the wind-up phenomenon. CHF3381 suppressed the maintenance of carrageenan-induced thermal and mechanical hyperalgesia in the rat with a minimum significantly effective dose (MED) of 30 mg/kg p.o. Memantine produced a partial reversal of both thermal and mechanical hyperalgesia (MED ϭ 10 and 15 mg/kg i.p., respectively). Gabapentin reversed mechanical hyperalgesia (MED ϭ 10 mg/kg s.c.), but did not affect thermal hyperalgesia. In the mouse formalin test, CHF3381 and memantine preferentially inhibited the late phase (MED ϭ 30 and 20 mg/kg i.p., respectively); gabapentin inhibited only the late phase (MED ϭ 30 mg/kg s.c.). Unlike morphine, CHF3381 chronic administration was not accompanied by the development of tolerance in the formalin test. Furthermore, morphine tolerance did not cross-generalize to CHF3381. In rats with a sciatic nerve injury, CHF3381 relieved both cold and mechanical allodynia (MED ϭ 100 mg/kg p.o.). In contrast, memantine was inactive. Gabapentin blocked cold allodynia (MED ϭ 30 mg/kg s.c.), but had marginal effects on mechanical allodynia. In diabetic neuropathy, CHF3381 reversed mechanical hyperalgesia (MED ϭ 50 mg/kg p.o.). Memantine (15 mg/kg i.p.) produced an antinociceptive effect, whereas gabapentin (100 mg/kg p.o.) had no significant effect. Thus, CHF3381 may be useful for the therapy of peripheral painful neuropathies.

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Section: Discussionsupporting

confidence: 74%

Antinociceptive Activity of the N-Methyl-d-aspartate Receptor Antagonist N-(2-Indanyl)-glycinamide Hydrochloride (CHF3381) in Experimental Models of Inflammatory and Neuropathic Pain

Villetti¹,

Bergamaschi²,

Bassani³

et al. 2003

J Pharmacol Exp Ther

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“…Doses of CP-101,606 were selected based on previous studies (Steece-Collier et al, 2000;Taniguchi et al, 1997). In these previous studies, CP-101,606 was effective at reducing haloperidol-induced catalepsy and neuropathic pain in rats over the dose range (2-20 mg/kg) used in the present study.…”

Section: Drug Treatmentmentioning

confidence: 96%

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

Nagy

Stoiljković

Menniti

et al. 2015

Neuropsychopharmacol

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Ketamine, a pan-NMDA receptor channel blocker, and CP-101,606, an NR2B-selective negative allosteric modulator, have antidepressant effects in humans that develop rapidly after the drugs are cleared from the body. It has been proposed that the antidepressant effect of ketamine results from delayed synaptic potentiation. To further investigate this hypothesis and potential mechanistic underpinnings we compared the effects of ketamine and CP-101,606 on neurophysiological biomarkers in rats immediately after drug administration and after the drugs had been eliminated. Local field and auditory-evoked potentials (AEPs) were recorded from primary auditory cortex and hippocampus in freely moving rats. Effects of different doses of ketamine or CP-101,606 were evaluated on amplitude of AEPs, auditory gating, and absolute power of delta and gamma oscillations 5-30 min (drug-on) and 5-6 h (drug-off) after systemic administration. Both ketamine and CP-101,606 significantly enhanced AEPs in cortex and hippocampus in the drug-off phase. In contrast, ketamine but not CP-101,606 disrupted auditory gating and increased gamma-band power during the drug-on period. Although both drugs affected delta power, these changes did not correlate with increase in AEPs in the drug-off phase. Our findings show that both ketamine and CP-101,606 augment AEPs after drug elimination, consistent with synaptic potentiation as a mechanism for antidepressant efficacy. However, these drugs had different acute effects on neurophysiological parameters. These results have implications for understanding the underlying mechanisms for the rapid-onset antidepressant effects of NMDA receptor inhibition and for the use of electrophysiological measures as translatable biomarkers.

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“…Preclinical pharmacological (Taniguchi et al, 1997;Boyce et al, 1999;Suetake-Koga et al, 2006) and genetic (Wei et al, 2001;Tan et al, 2005) studies indicate that GluN2B subunit-containing NMDA receptors may be specifically targeted to treat neuropathic pain (Chizh et al, 2001;Wu and Zhuo, 2009). Prompted by these data, the analgesic efficacy of a single dose of CP-101,606 was tested in a small number of patients suffering from pain due to spinal cord injury and monoradiculopathy, and a clinically meaningful reduction in reported pain was observed (Sang et al, 2003).…”

Section: N-methyl-d-aspartate Antagonistsmentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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Antinociceptive activity of CP‐101,606, an NMDA receptor NR2B subunit antagonist

Cited by 127 publications

References 7 publications

Antinociceptive Activity of the N-Methyl-d-aspartate Receptor Antagonist N-(2-Indanyl)-glycinamide Hydrochloride (CHF3381) in Experimental Models of Inflammatory and Neuropathic Pain

Antinociceptive Activity of the N-Methyl-d-aspartate Receptor Antagonist N-(2-Indanyl)-glycinamide Hydrochloride (CHF3381) in Experimental Models of Inflammatory and Neuropathic Pain

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

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