Phosphorylation of the <i>N</i>-methyl-d-aspartate receptor is increased in the nucleus accumbens during both acute and extended morphine withdrawal

Anderson, Ethan M.; Reeves, Turi; Kapernaros, Katherine; Neubert, John K.; Caudle, Robert M.

doi:10.1124/jpet.115.227629

Cited by 23 publications

(14 citation statements)

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“…infusion of GluN2B inhibitors prevents both acquisition and expression of morphine CPP (Ma et al ), and intra‐NAc shell GluN2B inhibition suppresses reinstatement of morphine CPP (Ma et al ). Also, repeated morphine increases NAc GluN1 surface levels and phosphorylation which lasts for months of withdrawal (Anderson et al ), suggesting that NMDAR changes are long‐lasting. Finally, since systemic and i.c.v.…”

Section: Nmdar Contributions To Opiate Addictionmentioning

confidence: 99%

Do specific NMDA receptor subunits act as gateways for addictive behaviors?

Hopf

2016

Genes Brain and Behavior

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Addiction to alcohol and drugs is a major social and economic problem, and there is considerable interest in understanding the molecular mechanisms that promote addictive drives. A number of proteins have been identified that contribute to expression of addictive behaviors. NMDA receptors (NMDARs), a subclass of ionotropic glutamate receptors, have been of particular interest because their physiological properties make them an attractive candidate for gating induction of synaptic plasticity, a molecular change thought to mediate learning and memory. NMDARs are generally inactive at the hyperpolarized resting potentials of many neurons. However, given sufficient depolarization, NMDARs are activated and exhibit long-lasting currents with significant calcium permeability. Also, in addition to stimulating neurons by direct depolarization, NMDARs and their calcium signaling can allow strong and/or synchronized inputs to produce long-term changes in other molecules (such as AMPA-type glutamate receptors) which can last from days to years, binding internal and external stimuli in a long-term memory trace. Such memories could allow salient drug-related stimuli to exert strong control over future behaviors and thus promote addictive drives. Finally, NMDARs may themselves undergo plasticity, which can alter subsequent neuronal stimulation and/or the ability to induce plasticity. This review will address recent and past findings suggesting that NMDAR activity promotes drug- and alcohol-related behaviors, with a particular focus on GluN2B subunits as possible central regulators of many addictive behaviors, as well as newer studies examining the importance of non-canonical NMDAR subunits and endogenous NMDAR cofactors.

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Section: Nmdar Contributions To Opiate Addictionmentioning

confidence: 99%

Do specific NMDA receptor subunits act as gateways for addictive behaviors?

Hopf

2016

Genes Brain and Behavior

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“…It has been shown that chronic opioid administration in rodents promoted GABA-mediated excitation [14] and loss of neuronal inhibition via reduction of KCC 2 currents in the ventral tegmental area [15]. Furthermore, acute morphine withdrawal in rats increased c-Fos expression in dopaminergic neurons within nucleus accumbens shell in mice [16], and phosphorylation of NMDARs in the accumbens [17]. These studies imply that neuronal hyperexcitability within the limbic regions may alter activity within the dopamine-dependent motivation system, thus producing aversive effects to opioid withdrawal and reinforcing future drug seeking behaviors.…”

Section: Central Mechanisms Of Opioid Withdrawalmentioning

confidence: 99%

Therapies and Mechanisms of Opioid Withdrawal

2017

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Opioids are revered as potent analgesics, yet their clinical utility for managing pain is shrouded by concerns over the high abuse potential. With skyrocketing numbers of opioid prescriptions and off-label use, and a striking number of accidental opioid-related deaths and emergency room visits, North America has declared an 'opioid crisis'. In the USA alone, the number of prescribed opioids has quadrupled since 1999, with enough opioid prescriptions dispensed annually to provide a bottle for every household [1]. The opioid crisis, however, is not an isolated North American problem as virtually all developed countries have reported increased opioid consumption and deaths. The alarming rise in opioid-related deaths has stoked growing concerns about the safety of opioids, and increased reluctance on the part of some physicians to prescribe this class of drugs. This has created a conundrum: on one hand, opioids are essential for managing pain, but an over-reliance on opioids can put patients at risk of serious adverse effects, such as opioid analgesic tolerance (diminished pain-relieving effects), hyperalgesia (paradoxical increase in pain sensitivity) and drug dependence (manifesting as drug craving, seeking and/or physical withdrawal). The problem of opioid withdrawalAlthough adverse effects undermine the long-term clinical utility of opioids for pain management, terminating opioid therapy is also problematic because it can precipitate a debilitating withdrawal syndrome in chronic users. In this respect, opioid withdrawal is a significant challenge in patients where pain has resolved and there is no longer a need for opioid treatment, or those that are on dangerously high doses and a reduction in dose is prudent. Depending on the half-life of the opioid used, withdrawal typically presents between 8 and 48 h after the last opioid dose, with symptoms including gastrointestinal discomfort, anxiety, insomnia, muscle cramps and hyperhidrosis [2]. Individuals are therefore compelled to continue using opioids to avoid these unpleasant somatic, autonomic and emotional symptoms. Thus opioid withdrawal is a key determinant for continued opioid use and a contributing factor for relapse. A potential complication of terminating opioid therapy is the re-emergence of pain or exacerbation of a preexisting pain condition. Although pain is a major concern, patients on opioid therapy report that mitigation of withdrawal is a more important consideration for continued opioid use than pain management [3]. However, discerning between pain from a pre-existing condition and pain arising from opioid withdrawal is difficult. Patients may demand higher doses of opioids to manage a perceived worsening of pain, but the underlying reason may stem from withdrawal rather than a progression of a pre-existing pain condition. Withdrawal is also a key motivating factor for continued opioid use in off-label or nonprescription opioid users, and like prescription opioid users, many of these individuals may be better positioned to stop opioid use if mor...

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“…There is increasing evidence suggesting that NMDAR in hippocampus, striatum, ventral tegmental area and nucleus accumbens is involved in morphine/opiate dependence [ 23 , 24 , 25 , 26 , 27 ]. It has been reported that the levels of NR2B were elevated in the hippocampus and nucleus accumbens in the morphine-dependent mice [ 8 , 23 ].…”

Section: Resultsmentioning

confidence: 99%

A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects

Liu¹,

Zheng²,

Yu³

et al. 2021

Marine Drugs

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N-methyl-D-aspartate receptor (NMDAR) antagonists have been found to be effective to inhibit morphine dependence. However, the discovery of the selective antagonist for NMDAR GluN2B with low side-effects still remains challenging. In the present study, we report a selective NMDAR GluN2B antagonist con-T[M8Q](a conantokin-T variant) that potently inhibits the naloxone-induced jumping and conditioned place preference of morphine-dependent mice at nmol/kg level, 100-fold higher than ifenprodil, a classical NMDAR NR2B antagonist. Con-T[M8Q] displays no significant impacts on coordinated locomotion function, spontaneous locomotor activity, and spatial memory mice motor function at the dose used. Further molecular mechanism experiments demonstrate that con-T[M8Q] effectively inhibited the transcription and expression levels of signaling molecules related to NMDAR NR2B subunit in hippocampus, including NR2B, p-NR2B, CaMKII-α, CaMKII-β, CaMKIV, pERK, and c-fos. The high efficacy and low side effects of con-T[M8Q] make it a good lead compound for the treatment of opiate dependence and for the reduction of morphine usage.

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Phosphorylation of the N-methyl-d-aspartate receptor is increased in the nucleus accumbens during both acute and extended morphine withdrawal

Cited by 23 publications

References 58 publications

Do specific NMDA receptor subunits act as gateways for addictive behaviors?

Do specific NMDA receptor subunits act as gateways for addictive behaviors?

Therapies and Mechanisms of Opioid Withdrawal

A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects

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