Opioid Regulation of Mu Receptor Internalisation: Relevance to the Development of Tolerance and Dependence

López-Giménez, Juan F.; Milligan, Graeme

doi:10.2174/187152710793361522

Cited by 12 publications

(13 citation statements)

References 68 publications

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“…Previous studies have shown that opioid receptors are [3,32,33] . After chronic or acute exposure to morphine, activated neurons and glia exhibit increased expression of pro-infl ammatory cytokines, such as TNF-α, IL-1β, IL-6 [19,34,35] , and chemokines [36,37] .…”

Section: Discussionmentioning

confidence: 97%

“…At the cellular level, morphine exerts its effects via G protein-coupled receptors, primarily μ-opioid receptors, resulting in the activation of intracellular signal-transduction kinases [3] . Nuclear factor-κB (NF-κB) is one of the most diverse and critical transcription factors that may either directly or indirectly transmit opioid receptor-mediated signals to the nucleus, and it regulates NF-κB-dependent gene expression in immune and non-immune cells [4] .…”

Section: Introductionmentioning

confidence: 99%

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Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

et al. 2014

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Nuclear factor kappa B (NF-κB) in the spinal cord is involved in pro-infl ammatory cytokine-mediated pain facilitation. However, the role of NF-κB activation in chronic morphine-induced analgesic tolerance and the underlying mechanisms remain unclear. In the present study, we found that the level of phosphorylated NF-κB p65 (p-p65) was increased in the dorsal horn of the lumbar 4-6 segments after intrathecal administration of morphine for 7 consecutive days, and the p-p65 was co-localized with neurons and astrocytes. The expression of TNF-α and IL-1β was also increased in the same area. In addition, pretreatment with pyrrolidinedithiocarbamate (PDTC) or SN50, inhibitors of NF-κB, prevented the development of morphine analgesic tolerance and alleviated morphine withdrawal-induced allodynia and hyperalgesia. The increase in TNF-α and IL-1β expression induced by chronic morphine exposure was also partially blocked by PDTC pretreatment. In another experiment, rats receiving PDTC or SN50 beginning on day 7 of morphine injection showed partial recovery of the anti-nociceptive effects of morphine and attenuation of the withdrawal-induced abnormal pain. Meanwhile, intrathecal pretreatment with lipopolysaccharide from Rhodobacter sphae roides, an antagonist of toll-like receptor 4 (TLR4), blocked the activation of NF-κB, and prevented the development of morphine tolerance and withdrawalinduced abnormal pain. These data indicated that TLR4-mediated NF-κB activation in the spinal cord is involved in the development and maintenance of morphine analgesic tolerance and withdrawalinduced pain hypersensitivity.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

et al. 2014

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“…In addition, Morphine realize it analgesic function trough targeting μ opioid receptor (MOR). Desensitization and trafficking of μ opioid receptor has been widely accepted as a main reason for morphine tolerance [39–41]. By regulating such transcription factors of OPRM (MOR gene) as NF-κB through different pathways, miR-93 and Smad5 may participate in the formation of morphine tolerance [36, 42].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-93-5p may participate in the formation of morphine tolerance in bone cancer pain mouse model by targeting Smad5

Xiao

Lou

et al. 2016

Oncotarget

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ObjectiveIn this study, we aim to find out the role of microRNA-93-5p (miR-93) and Smad5 in morphine tolerance in mouse models of bone cancer pain (BCP).ResultsAt 7 days after injection of morphine, the PMWT showed no significant difference between the morphine model group and the saline model group (P < 0.05), suggesting that morphine tolerance had formed in the morphine model group. The morphine model group had higher miR-93 expression and lower Smad5 mRNA expression than the saline model group. Smad5 is a downstream target gene of miR-93. At 7, 9 and 14 days after injection of lentiviruses, the L/anti-miR-93 group had the lowest PMWTs, while the Smad5 shRNA group presented the highest PMWTs among these five groups (all P < 0.05).MethodsWe built mouse models of BCP and morphine tolerance and recorded 50% PMWT. After 6 days of modeling, we set saline control group, morphine control, saline model group and morphine model group (morphine tolerance emerged). We performed luciferase reporter gene assay to verify the relation between miR-93 and Smad5. After lentivirus transfection, the mice with morphine tolerance were assigned into L/anti-miR-93 group, Smad5 shRNA group, L/anti-miR-93 + Smad5 shRNA group, blank group and PBS control group. RT-qPCR, Western Blot assay and immumohistochemical staining were performed to observe the changes of miR-93 and Smad5.ConclusionUp-regulation of miR-93 may contribute to the progression of morphine tolerance by targeting Smad5 in mouse model of BCP.

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“…In contrast, during chronic opiate use, the brain adapts, restricting the effects of opiates by internalization of opiate receptors. 36 This idea is supported by behavioral findings, demonstrating better executive functioning and visuospatial abilities in the patients who received long-term methadone treatment (6 months) compared to the patients receiving shortterm treatment (30 days). 37 …”

Section: Higher Bold Response During Spatial Working Memory Task In Tmentioning

confidence: 80%

Diminished Brain Functional Magnetic Resonance Imaging Activation in Patients on Opiate Maintenance Despite Normal Spatial Working Memory Task Performance

Bach¹,

Vollstädt‐Klein²,

Frischknecht³

et al. 2012

Clinical Neuropharmacology

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Opioid Regulation of Mu Receptor Internalisation: Relevance to the Development of Tolerance and Dependence

Cited by 12 publications

References 68 publications

Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

MicroRNA-93-5p may participate in the formation of morphine tolerance in bone cancer pain mouse model by targeting Smad5

Diminished Brain Functional Magnetic Resonance Imaging Activation in Patients on Opiate Maintenance Despite Normal Spatial Working Memory Task Performance

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