IRAS Modulates Opioid Tolerance and Dependence by Regulating μ Opioid Receptor Trafficking

Li, Fēi; Ma, Hao; Wu, Ning; Li, Jin

doi:10.1007/s12035-015-9417-6

Cited by 13 publications

(9 citation statements)

References 33 publications

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“…user. The amount of mu receptor and rate of receptor internalization have been set to represent a subject with opioid tolerance [26,27]. Model simulations illustrate the time course of fentanyl concentration in plasma and brain, naloxone concentration in plasma and brain, and fentanyl and naloxone mu receptor…”

Section: Methodsmentioning

confidence: 99%

Higher naloxone dosing in a quantitative systems pharmacology model that predicts naloxone-fentanyl competition at the opioid mu receptor level

et al. 2020

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Rapid resuscitation of an opioid overdose with naloxone, an opioid antagonist, is critical. We developed an opioid receptor quantitative systems pharmacology (QSP) model for evaluation of naloxone dosing. In this model we examined three opioid exposure levels that have been reported in the literature (25 ng/ml, 50 ng/ml, and 75 ng/ml of fentanyl). The model predicted naloxone-fentanyl interaction at the mu opioid receptor over a range of three naloxone doses. For a 2 mg intramuscular (IM) dose of naloxone at lower fentanyl exposure levels (25 ng/ml and 50 ng/ml), the time to decreasing mu receptor occupancy by fentanyl to 50% was 3 and 10 minutes, respectively. However, at a higher fentanyl exposure level (75 ng/ml), a dose of 2 mg IM of the naloxone failed to reduce mu receptor occupancy by fentanyl to 50%. In contrast, naloxone doses of 5 mg and 10 mg IM reduced mu receptor occupancy by fentanyl to 50% in 5.5 and 4 minutes respectively. These results suggest that the current doses of naloxone (2 mg IM or 4 mg intranasal (IN)) may be inadequate for rapid reversal of toxicity due to fentanyl exposure and that increasing the dose of naloxone is likely to improve outcomes.

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Section: Methodsmentioning

confidence: 99%

Higher naloxone dosing in a quantitative systems pharmacology model that predicts naloxone-fentanyl competition at the opioid mu receptor level

et al. 2020

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“…1B-D). Together, these data suggest that Nischarin promotes translocation of GLT-1 from the surface to intracellular compartments, but (in contrast to its effect on mu opioid receptors: Li et al, 2016) does not affect GLT-1 recycling.…”

Section: Resultsmentioning

confidence: 75%

“…Nischarin has been shown to alter the surface levels of receptors, including integrins and mu opioid receptors (Li et al, 2019, Li et al, 2016, Lim and Hong, 2004). To determine whether Nischarin regulated GLT-1 surface density, we used an ‘antibody feeding’ immunofluorescence internalization assay in HeLa cells to visualize GLT-1 trafficking.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we have identified the non-adrenergic imidazoline-1 receptor protein Nischarin, as a novel physiological GLT-1 N-terminus interacting protein in astrocytes. Nischarin is a cytoplasmic protein that shows a diverse set of functions, including regulation of the cytoskeletal network (through Rac1), interaction with endosomes (via its phox domain), and regulation of receptor (mu opioid and integrin α 5 receptors) surface levels (Alahari et al, 2000, Keller et al, 2017, Li et al, 2016, Kuijl et al, 2013, Alahari et al, 2004, Alahari, 2003, Dong et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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The non-adrenergic imidazoline-1 receptor protein Nischarin is a key regulator of astrocyte glutamate uptake

Gupta‐Agarwal

Bazargani

Drew

et al. 2020

Preprint

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SummaryAstrocytic GLT-1 is the main glutamate transporter involved in glutamate buffering in the brain, pivotal for glutamate removal at excitatory synapses to terminate neurotransmission and for preventing excitotoxicity. We show here that the surface expression and function of GLT-1 can be rapidly modulated through the interaction of its N-terminus with the nonadrenergic imidazoline-1 receptor protein, Nischarin. The phox domain of Nischarin is critical for interaction and internalization of surface GLT-1. Using live super-resolution imaging, we found that glutamate accelerated Nischarin-GLT-1 internalization into endosomal structures. The surface GLT-1 level increased in Nischarin knockout astrocytes, and this correlated with a significant increase in transporter uptake current. Furthermore, Nischarin knockout in astrocytes is neuroprotective against glutamate excitotoxicity. These data provide new molecular insights into regulation of GLT-1 surface level and function and suggest novel drug targets for the treatment of neurological disorders.HighlightsThe phox domain of Nischarin interacts with the N-terminal tail of the main astrocyte glutamate transporter, GLT-1.Nischarin promotes internalization of GLT-1 to endosomes.Glutamate modulates GLT-1 surface levels via regulation of the Nischarin-GLT-1 interaction.Genetic loss of Nischarin significantly increases GLT-1 surface expression, resulting in increased glutamate transport currents and enhanced neuroprotection.

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“… 16 , 17 GPCR-associated sorting protein binds the cytoplasmic tail of DOR and targets DORs to lysosomes, while imidazoline receptor antisera-selected protein modulates MOR and sorts MORs to the recycling pathway. 18 – 20 However, our previous study reveals that the post-endocytic MOR/DOR heteromers are processed in proteasomes or lysosomes for degradation following the DOR agonist stimulation, resulting in the reduction of MORs on the cell surface. 21 The MOR/DOR heteromers, but not MORs alone, are able to recruit β-arrestin2.…”

Section: Introductionmentioning

confidence: 93%

Clinical opioids differentially induce co-internalization of μ- and δ-opioid receptors

Bao

Chen

et al. 2018

Mol Pain

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Opioid receptors play an important role in mediating the spinal analgesia. The μ-opioid receptor is the major target of opioid drugs widely used in clinics. However, the regulatory mechanisms of analgesic effect and tolerance for clinical μ-opioid receptor-targeting opioids remain to be fully investigated. Previous studies showed the interaction of δ-opioid receptor with μ-opioid receptor to form the μ-opioid receptor/δ-opioid receptor heteromers that could be processed in the degradation pathway after δ-opioid receptor agonist treatment. Here, we showed that clinical μ-opioid receptor-targeting opioids, morphine, fentanyl, and methadone, but not tramadol, caused μ-opioid receptor co-internalization with δ-opioid receptors in both transfected human embryonic kidney 293 cells and primary sensory neurons. Prolonged treatment of morphine led to μ-opioid receptor co-degradation with δ-opioid receptors. Furthermore, fentanyl and methadone, but not tramadol, induced the drug tolerance similar to morphine. Thus, the clinical μ-opioid receptor-targeting opioids including morphine, fentanyl, and methadone induce μ-opioid receptor co-internalization with δ-opioid receptors, which may be involved in the analgesic tolerance of these opioids.

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IRAS Modulates Opioid Tolerance and Dependence by Regulating μ Opioid Receptor Trafficking

Cited by 13 publications

References 33 publications

Higher naloxone dosing in a quantitative systems pharmacology model that predicts naloxone-fentanyl competition at the opioid mu receptor level

Higher naloxone dosing in a quantitative systems pharmacology model that predicts naloxone-fentanyl competition at the opioid mu receptor level

The non-adrenergic imidazoline-1 receptor protein Nischarin is a key regulator of astrocyte glutamate uptake

Clinical opioids differentially induce co-internalization of μ- and δ-opioid receptors

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