Allosteric modulation of the NMDA receptor by neurosteroids in rat brain and the impact of long term morphine administration

Johansson, Tobias; Elfverson, Martin; Zhou, Qin; Nyberg, Fred

doi:10.1016/j.bbrc.2010.09.073

Cited by 22 publications

(11 citation statements)

References 26 publications

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“…To overcome tolerance and achieve equivalent pain relief, the opioid dose is progressively escalated which can exacerbate the unwanted effects (Thorn et al, 2015). Mechanisms of tolerance are complex and involves changes in receptors, ion channels cell and neuronal networks functions (Ji, 2010; Johansson et al, 2010; Zhang et al, 2015). According to a classical view these re-arrangements occur at the neuronal level, however growing evidence indicates a potential role of glia cells that are activated by repeated administrations of morphine (Di Cesare Mannelli et al, 2015; Horvath et al, 2009; Mika, 2008; Mika et al, 2009; Raghavendra et al, 2003; Song and Zhao, 2001; Watkins et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Involvement of the N/OFQ-NOP system in rat morphine antinociceptive tolerance: Are astrocytes the crossroad?

Micheli

Lucarini

Corti

et al. 2018

European Journal of Pharmacology

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The development of tolerance to the antinociceptive effect is a main problem associated with the repeated administration of opioids. The progressively higher doses required to relieve pain reduce safety and exacerbate the side effects of classical opioid receptor agonists like morphine. Nociceptin/orphanin FQ (N/OFQ) and its NOP receptor constitute the fourth endogenous opioid system that is involved in the control of broad spectrum of biological functions, including pain transmission. Aim of this work was to evaluate the relevance of the N/OFQ-NOP system in morphine antinociceptive action and in the development of morphine tolerance in the rat. Continuous spinal intrathecal infusion of morphine (1 – 3 nmol/h) evoked analgesic effects for 5 days in wild type animals. The same doses infused in NOP(−/−) rats showed a lower analgesic efficacy, while the onset of tolerance was delayed to day 9. N/OFQ (1 – 3 nmol/h), continuously infused in NOP(+/+) animals, showed an analgesic profile similar to morphine. Immunohistochemical analysis of the dorsal horn of the spinal cord of morphine tolerant NOP(+/+) rats showed an increased number of Iba1- and GFAP-positive cells (microglia and astrocytes, respectively). Interestingly, microglia but not astrocyte activation was observed in NOP(−/−) morphine tolerant rat. A selective activation of astrocytes was observed in the dorsal horn of wild type N/OFQ tolerant rats. The antinociceptive effect of morphine partially depends by the N/OFQ-NOP system that participates in the development of morphine tolerance. In particular, NOP receptors are involved in morphine-induced astrocyte activation, and N/OFQ per se increases astrocyte density.

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Section: Introductionmentioning

confidence: 99%

Involvement of the N/OFQ-NOP system in rat morphine antinociceptive tolerance: Are astrocytes the crossroad?

Micheli

Lucarini

Corti

et al. 2018

European Journal of Pharmacology

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“…Chronic exposure to morphine markedly decreases the expression of the NR2B subunit in the nucleus accumbens [45], frontal cortex, and striatum [45]. In rat hippocampus and hypothalamus, chronic morphine treatment fails to affect the allosteric binding but significantly decreases the expression of NR2B [46][47][48]. In the present study, we showed that in the hippocampus of chronic morphine-treated rats, expression of the NR2B subunit, but not the NR1 subunit, was significantly downregulated, and agmatine reversed this change.…”

Section: Discussionmentioning

confidence: 97%

Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats

Wang¹,

Zhao

et al. 2016

Neurosci. Bull.

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Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hippocampal extracellular glutamate level induced by naloxone (2 mg/kg, i.p.) precipitation. Agmatine (20 mg/kg, s.c.) administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synaptosomes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agmatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors (NMDARs) was downregulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine prevented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including modulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.

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“…Long-term treatment of rats with morphine resulted in an increase in specific binding of [ 3 H]ifenprodil in frontal cortex and not the hippocampus or hypothalamus, suggesting a biologically relevant specific upregulation or unblocking of NR2B receptors (Johansson et al 2010). The effects of PregS and DHEAS on [ 3 H]ifenprodil binding to membrane homogenates were unaffected by morphine treatment, while the PAS binding profile in cortex was altered, suggesting a change in NR2B receptors affecting PAS but not PregS or DHEAS allosteric modulation of the receptor (Johansson et al 2010).…”

Section: Evidence For Meeting the Criteria For Neurotransmitter Actionmentioning

confidence: 99%

“…The effects of PregS and DHEAS on [ 3 H]ifenprodil binding to membrane homogenates were unaffected by morphine treatment, while the PAS binding profile in cortex was altered, suggesting a change in NR2B receptors affecting PAS but not PregS or DHEAS allosteric modulation of the receptor (Johansson et al 2010). Overall, the results provide compelling evidence that picomolar to nanomolar concentrations of PregS interact with the NMDAR via an indirect circuitry level pathway or direct modulatory mechanism.…”

Section: Evidence For Meeting the Criteria For Neurotransmitter Actionmentioning

confidence: 99%

Pregnenolone sulfate as a modulator of synaptic plasticity

2014

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Rationale The neurosteroid pregnenolone sulfate (PregS) acts as a cognitive enhancer and modulator of neurotransmission, yet aligning its pharmacological and physiological effects with reliable measurements of endogenous local concentrations and pharmacological and therapeutic targets has remained elusive for over 20 years. Objectives New basic and clinical research concerning neurosteroid modulation of the central nervous system (CNS) function has emerged over the past 5 years, including important data involving pregnenolone and various neurosteroid precursors of PregS that point to a need for a critical status update. Results Highly specific actions of PregS affecting excitatory N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic transmission and the pharmacological effects of PregS on various receptors and ion channels are discussed. The discovery of a high potency (nanomolar) signal transduction pathway for PregS-induced NMDAR trafficking to the cell surface via a Ca2+- and G protein-coupled receptor (GPCR)-dependent mechanism and a potent (EC50 ~2 pM) direct enhancement of intracellular Ca2+ levels is discussed in terms of its agonist effects on long-term potentiation (LTP) and memory. Lastly, preclinical and clinical studies assessing the promnestic effects of PregS and pregnenolone toward cognitive dysfunction in schizophrenia, and altered serum levels in epilepsy and alcohol dependence, are reviewed. Conclusions PregS is present in human and rodent brain at physiologically relevant concentrations and meets most of the criteria for an endogenous neurotransmitter/neuromodulator. PregS likely plays a significant role in modulation of glutamatergic excitatory synaptic transmission underlying learning and memory, yet the molecular target(s) for its action awaits identification.

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Allosteric modulation of the NMDA receptor by neurosteroids in rat brain and the impact of long term morphine administration

Cited by 22 publications

References 26 publications

Involvement of the N/OFQ-NOP system in rat morphine antinociceptive tolerance: Are astrocytes the crossroad?

Involvement of the N/OFQ-NOP system in rat morphine antinociceptive tolerance: Are astrocytes the crossroad?

Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats

Pregnenolone sulfate as a modulator of synaptic plasticity

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