Peripherally acting NMDA receptor/glycine site receptor antagonists inhibit morphine tolerance

Danysz, Wojciech; Kozela, Ewa; Parsons, Chris G.; Sladek, Meik; Bauer, Tanja; Popik, Piotr

doi:10.1016/j.neuropharm.2004.11.005

Cited by 23 publications

(22 citation statements)

References 38 publications

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“…However, the antagonists of NMDA or GABA receptors did not reverse the antinociceptive effects of gabapentin in animal pain models (21,26,58,59,68). In addition, NMDA-receptor antagonists shared the same actions of gabapentin in inhibiting morphine tolerance (49,93) and potentiating morphine analgesia (94,95). Therefore, it is unlikely that gabapentin acts as an NMDA-receptor enhancer to exert its analgesic effect.…”

Section: -2 Glutamatergic System 4-2-1 Ampa Receptorsmentioning

confidence: 99%

Mechanisms of the Antinociceptive Action of Gabapentin

2006

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Abstract. Gabapentin, a γ-aminobutyric acid (GABA) analogue anticonvulsant, is also an effective analgesic agent in neuropathic and inflammatory, but not acute, pain systemically and intrathecally. Other clinical indications such as anxiety, bipolar disorder, and hot flashes have also been proposed. Since gabapentin was developed, several hypotheses had been proposed for its action mechanisms. They include selectively activating the heterodimeric GABA B receptors consisting of GABA B1a and GABA B2 subunits, selectively enhancing the NMDA current at GABAergic interneurons, or blocking AMPA-receptor-mediated transmission in the spinal cord, binding to the L-α-amino acid transporter, activating ATP-sensitive K + channels, activating hyperpolarization-activated cation channels, and modulating Ca 2+ current by selectively binding to the specific binding site of [3 H]gabapentin, the α 2 δ subunit of voltage-dependent Ca 2+ channels. Different mechanisms might be involved in different therapeutic actions of gabapentin. In this review, we summarized the recent progress in the findings proposed for the antinociceptive action mechanisms of gabapentin and suggest that the α 2 δ subunit of spinal N-type Ca 2+ channels is very likely the analgesic action target of gabapentin.

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Section: -2 Glutamatergic System 4-2-1 Ampa Receptorsmentioning

confidence: 99%

Mechanisms of the Antinociceptive Action of Gabapentin

2006

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“…Thus, the reversal of tolerance would be mediated by the same mechanism as indicated previously for noncompetitive NMDA receptor antagonists (Trujillo and Akil, 1991). It was reported that selective NMDA receptor antagonists attenuated the development of morphine tolerance (Hamdy et al, 2004;Danysz et al, 2005). Stimulation of NMDA receptors was shown to disinhibit GSK3␤ by PPI-mediated dephosphorylation of GSK3␤ at the Ser 9 (Szatmari et al, 2005).…”

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confidence: 67%

Effects of Glycogen Synthase Kinase 3β and Cyclin-Dependent Kinase 5 Inhibitors on Morphine-Induced Analgesia and Tolerance in Rats

Parkitna

Obara²,

Wawrzczak-Bargieła³

et al. 2006

J Pharmacol Exp Ther

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Repeated administration of morphine is associated with the development of tolerance, yet the mechanism underlying this phenomenon is still poorly understood. Recent evidence implicating glycogen synthase kinase 3 (GSK3) in opioid receptor signaling pathways has prompted us to investigate its role in morphine tolerance. Administration of 10 mg/kg morphine i.p. to Wistar rats twice daily for 8 days resulted in complete tolerance to its analgesic effects as measured by the tail-flick test. When injections of morphine were preceded by intrathecal (i.t.) administration of either an inhibitor of GSK3 [(3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763) or 6-bromoindirubin-3Јoxime] or an inhibitor of cyclin-dependent kinase (Cdk), roscovitine, development of tolerance to morphine analgesia was completely abolished. In addition, a single i.t. injection of either kinase inhibitor was able to restore in a dose-dependent manner the analgesic effect of morphine in morphine-tolerant rats. None of the inhibitors in doses used in the present study had analgesic effects of their own nor an effect on the analgesic potency of morphine. Repeated i.t. administration of either inhibitor had caused an increase in abundance of GSK-3␤ phosphorylated at Ser 9 in the dorsal lumbar part of the spinal cord of rats that were chronically treated with morphine. Furthermore, reversal of morphine tolerance by a single injection of either inhibitor was always associated with increased abundance of phospho-GSK3␤. In conclusion, our data indicate that chronic morphine treatment activates a highly efficient pathway by means of which Cdk5 regulates GSK3␤ activity.Adaptations in cellular signaling evoked by repeated morphine administration that lead to development of tolerance are still unclear. Binding of morphine to its main target, the -opioid receptor, results in the activation of a G i/o protein, inhibition of adenylate cyclases, and downregulation of the cAMP second messenger pathway. Prolonged exposure to morphine or specific -opioid receptor agonists has an opposite effect and leads to up-regulation of the cAMP pathway, possibly through the actions of the ␤␥ subunits of G i/o proteins (Tan et al., 2003), although the involvement of regulators of G protein signaling (RGS proteins) was also indicated (Gold et al., 2003). It was reported that morphine could activate the mitogen-activated protein kinase cascade (Berhow et al., 1996;Bohn et al., 2000;Bilecki et al., 2004;Muller and Unterwald, 2004) with the involvement of the phosphoinositol-3-kinase and protein kinase C kinases (Tan et al., 2003;Belcheva et al., 2005). Activation of the phosphoinositol-3-kinase also led to phosphorylation of Akt and other down-stream effectors (Polakiewicz et al., 1998;Iglesias et al., 2003;Muller and Unterwald, 2004). Recent evidence points to the possibil-

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“…), and glycine site/NMDA antagonists (ACPC, l-701324, MRZ2/570, etc.) could block the development of morphine-induced conditioned place preference (Xi and Stein, 2002;Danysz et al, 2005;Makarska-Bialek et al, 2005;Bäckström and Hyytia, 2006;Quartaroli et al, 2001), the involved molecular mechanism is still unknown. To date, molecular and cloning studies revealed that the NMDA receptor is a channel-bearing protein complex which exists as a tetramer or pentamer.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of the NMDA receptor requires the simultaneous binding of two agonists: glutamate and glycine (Pláteník et al, 2000). Both competitive and uncompetitive NMDA receptor antagonists have been found to inhibit the conditioned place preference (CPP) induced by morphine, amphetamine and cocaine (Xi and Stein, 2002;Danysz et al, 2005;Makarska-Bialek et al, 2005;Bäckström and Hyytia, 2006), suggesting a possible role in the treatment of drug addiction. But most of both classes of NMDA receptor antagonists have been reported to produce severe psycho-stimulant and psychotomimetic-like effects in animal and clinical experiments.…”

Section: Introductionmentioning

confidence: 99%

Effect of glycine site/NMDA receptor antagonist MRZ2/576 on the conditioned place preference and locomotor activity induced by morphine in mice

Zhu

Long

Zheng

et al. 2006

J. Zhejiang Univ. - Sci. B

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Objective: To study the effect of glycine site/NMDA (N-methyl-D-aspartate) receptor antagonist MRZ2/576 on the conditioned place preference (CPP) and locomotor activity induced by morphine in mice. Methods: Different doses (1.25, 2.5 and 5 mg/kg, i.p.) of MRZ2/576 were used to evaluate the effect of MRZ2/576 on the acquisition and expression of CPP induced by morphine (5 mg/kg) in mice. In addition, we examined the locomotor activity of mice in conditioning and testing phase of CPP paradigm. Results: MRZ2/576 alone could not establish place preference, but a 5 mg/kg dose of MRZ2/576 could block both acquisition and expression of morphine-induced CPP. In testing phase of CPP, there was no statistical difference for locomotor activity between the groups; injection of MRZ2/576 showed a dose-dependent decrease of locomotor activity on both control and morphine-treated mice, especially 5 mg/kg of MRZ2/576 significantly suppressed the locomotor activity of mice. Conclusion: Based on the present results, we assume that MRZ2/576 can antagonize the rewarding effect of morphine, suggesting that this glycine site/NMDA receptor antagonist could be used to treat addictions due to its light side effect profile.

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Peripherally acting NMDA receptor/glycine site receptor antagonists inhibit morphine tolerance

Cited by 23 publications

References 38 publications

Mechanisms of the Antinociceptive Action of Gabapentin

Mechanisms of the Antinociceptive Action of Gabapentin

Effects of Glycogen Synthase Kinase 3β and Cyclin-Dependent Kinase 5 Inhibitors on Morphine-Induced Analgesia and Tolerance in Rats

Effect of glycine site/NMDA receptor antagonist MRZ2/576 on the conditioned place preference and locomotor activity induced by morphine in mice

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