Loss of the mu opioid receptor induces strain-specific alterations in hippocampal neurogenesis and spatial learning

Cominski, Tara P.; Ansonoff, Micheal; Turchin, C.E.; Pintar, John E.

doi:10.1016/j.neuroscience.2014.07.039

Cited by 6 publications

(4 citation statements)

References 50 publications

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“…Moreover, the facilitative effect of 6-β-naltrexol, a MOR neutral antagonist (40,41), on learning in wild-type mice (Supplemental Figure S1) confirms that naltrexone acts as a neutral antagonist to induce its effect. The similarities of performances between the saline-treated wild-type and MORKO mice during the acquisition and the first probe are in line with previous studies in which the same genetic background and mutation were used (42,43,44). …”

Section: Discussionsupporting

confidence: 86%

Naltrexone Facilitates Learning and Delays Extinction by Increasing AMPA Receptor Phosphorylation and Membrane Insertion

Kibaly

Kam

Loh

et al. 2016

Biological Psychiatry

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Background The opioid antagonists, naloxone/naltrexone, are involved in improving learning and memory, but their cellular and molecular mechanisms remain unknown. We investigated the effect of naloxone/naltrexone on hippocampal AMPAR trafficking, a molecular substrate of learning and memory, as a probable mechanism for the antagonists activity. Methods To measure naloxone/naltrexone-regulated AMPAR trafficking, pHluorin-GluA1 imaging and biochemical analyses were performed on primary hippocampal neurons. To establish the in vivo role of GluA1-S845 phosphorylation on the behavioral effect induced by inhibition of the endogenous μ-opioid receptor (MOR) by naltrexone, MOR knockout (MORKO) and GluA1-S845A mutant (in which Ser845 was mutated to Ala) mice were tested in a water maze after chronic naltrexone administration. Behavioral responses and GluA1 levels in the hippocampal postsynaptic density (PSD) in wild-type and GluA1-S845A mutants mice were compared using Western blot analysis. Results In vitro prolonged naloxone/naltrexone exposure significantly increased synaptic and extrasynaptic GluA1 membrane expression as well as GluA1-S845 phosphorylation. In the MORKO and GluA1-S845A mutant mice, naltrexone did not improve learning, which suggests that naltrexone acts via inhibition of endogenous MOR action and alteration of GluA1 phosphorylation. Naltrexone-treated wild-type mice had significantly increased phosphorylated GluA1-S845 and GluA1 levels in their hippocampal PSD on the third day of acquisition, which is the time when naltrexone significantly improved learning. Conclusions The beneficial effect of naltrexone on spatial learning and memory under normal conditions appears to be the result of increasing GluA1-S845 phosphorylation-dependent AMPAR trafficking. These results can be further explored in a mouse model of memory loss.

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Section: Discussionsupporting

confidence: 86%

Naltrexone Facilitates Learning and Delays Extinction by Increasing AMPA Receptor Phosphorylation and Membrane Insertion

Kibaly

Kam

Loh

et al. 2016

Biological Psychiatry

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“…The role of the endogenous opioid tone inhibition in enhancing spatial learning is questioned by the behavioural discrepancies between the genetic backgrounds and mutations of knockout animals. Studies using MOP−/− mice with a 100% C57BL/6 background and MOP exon 1 excised exhibited intact acquisition and first retrieval 86,89–91 . By contrast, MOP−/− mice with a hybrid genetic background (that is, 50% 129SVJ and 50% C57BL/6 or 129/Ola-C57BL/6) or MOP exons 2and 3 deleted displayed impaired spatial learning 57,92,93 .…”

Section: Opioid System Learning and Memorymentioning

confidence: 98%

Non-nociceptive roles of opioids in the CNS: opioids’ effects on neurogenesis, learning, memory and affect

Kibaly

Cahill

et al. 2018

Nat Rev Neurosci

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Mortality due to opioid use has grown to the point where, for the first time in history, opioid-related deaths exceed those caused by car accidents in many states in the United States. Changes in the prescribing of opioids for pain and the illicit use of fentanyl (and derivatives) have contributed to the current epidemic. Less known is the impact of opioids on hippocampal neurogenesis, the functional manipulation of which may improve the deleterious effects of opioid use. We provide new insights into how the dysregulation of neurogenesis by opioids can modify learning and affect, mood and emotions, processes that have been well accepted to motivate addictive behaviours.

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“…Semi-synthetic/synthetic opioids and opiates commonly act on opioid receptors of the subtypes mu, kappa, or delta and each of these three opioid receptors has been found in the hippocampus (Polunina & Bryun, 2013). Studies have found that opioid binding to these receptors has a negative impact on adult hippocampal functioning (Wang & Han, 2009;Cominski, Ansonoff, Turchin, & Pintar, 2014). Furthermore, studies have shown that opioid receptor University of Saskatchewan Undergraduate Research Journal 3…”

Section: Opioid Binding In the Hippocampusmentioning

confidence: 99%

“…antagonists, such as naloxone and naltrexone, have a positive impact on adult hippocampal functioning (Cominski et al, 2014). Therefore, it is suggested that opioid binding plays a role in hippocampal-associated learning and memory.…”

Section: Opioid Binding In the Hippocampusmentioning

confidence: 99%

Neurodevelopmental Changes in Offspring Prenatally Exposed to Opioids in Human Children and Rodent Models: A Review

Quagraine¹

2019

USURJ

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The number of infants born to opioid-dependent pregnant women in North America is a growing problem. Studies that focus on the long-term effects of neurodevelopmental changes of prenatal opioid exposure in human infants are however limited. The use of rodent models to evaluate these changes may provide some insight. This review focuses on studies of rodent models exposed to opioids such as morphine, heroin, oxycodone, buprenorphine, methadone, and l-α-acetylmethadol in uteroand briefly discusses the neural and behavioural effects in human children. Most of the rodent studies reported the following neural effects: increases in caspase-3 and Bax/Bcl-2 ratio, altered NMDA activity, and decreases in BDNF expression in the offspring prenatally exposed to opioids. In addition, they showed decreases in synaptic plasticity, LTP, LTD, dendritic length, and dendritic branch number. The exposed rodent offspring were more inclined to perform poorly in the behavioural tests. Likewise, some of the human studies reported a significant difference between the exposed group and the control; however, other studies reported insignificant or no significant differences after correcting for covariates. Most of the studies suggest an impairment in learning and memory in the rodent offspring and deficits in behaviour and cognition in human children; however, this was not always the case. It is still not clear whether the effects of prenatal opioid exposure are due to the opioid itself being the prime factor, as various factors may also contribute to the results. Further studies of the effects of early opioid exposure on neurodevelopment in the offspring are required.

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Loss of the mu opioid receptor induces strain-specific alterations in hippocampal neurogenesis and spatial learning

Cited by 6 publications

References 50 publications

Naltrexone Facilitates Learning and Delays Extinction by Increasing AMPA Receptor Phosphorylation and Membrane Insertion

Naltrexone Facilitates Learning and Delays Extinction by Increasing AMPA Receptor Phosphorylation and Membrane Insertion

Non-nociceptive roles of opioids in the CNS: opioids’ effects on neurogenesis, learning, memory and affect

Neurodevelopmental Changes in Offspring Prenatally Exposed to Opioids in Human Children and Rodent Models: A Review

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