Enhancement of morphine analgesia and prevention of morphine tolerance by downregulation of β-arrestin 2 with antigene RNAs in mice

Bu, Huilian; Liu, Xijiang; Tian, Xiaojing; Yang, Hui; Gao, Feng

doi:10.3109/00207454.2014.896913

Cited by 24 publications

(17 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Constitutive deletion of barr2 resulted in viable mice on an S129/C57BL/6 background, and initial experiments with morphine revealed both enhanced potency and extended duration of action in the hot plate assay, a measure of supraspinally mediated antinociception (8)(9)(10), and in the warm water tail immersion assay, a measure of spinal reflex to nociceptive stimuli (11,12). These behavioral results have also been observed in mice treated intracerebroventricularly with via antigene RNA inhibition of barr2 (13). Mice injected with short interfering RNA (siRNA) to barr2 but not to barr1 into the periaqueductal gray showed enhanced and prolonged antinociception, while overexpression of barr2 but not of barr1 inhibited morphine-induced antinociception in the hot plate test (14).…”

Section: Genetically Modified Mouse Models As Indicators Of Physiologmentioning

confidence: 79%

Toward Directing Opioid Receptor Signaling to Refine Opioid Therapeutics

Grim

Acevedo‐Canabal

Bohn

2020

Biological Psychiatry

View full text Add to dashboard Cite

The mu opioid receptor (MOR) is a diversely regulated target for the alleviation of pain in the clinical setting. However, untoward side effects such as tolerance, dependence, respiratory suppression, constipation, and abuse liability detract from the general activation of these receptors. Studies in genetically modified rodent models suggest that activating G protein signaling pathways while avoiding phosphorylation of the receptor or recruitment of b-arrestin scaffolding proteins could preserve the analgesic properties of MOR agonists while avoiding certain side effects. With the development of novel MOR "biased" agonists, which lead to preferential activation of G protein pathways over receptor phosphorylation, internalization, or interaction with other effectors, this hypothesis can be tested in a native, physiological setting. Overall, it is clear that the MOR is not a simple on-off switch and that the diverse means by which the receptor can be regulated may present an opportunity to refine therapeutics for the treatment of pain.

show abstract

Section: Genetically Modified Mouse Models As Indicators Of Physiologmentioning

confidence: 79%

Toward Directing Opioid Receptor Signaling to Refine Opioid Therapeutics

Grim

Acevedo‐Canabal

Bohn

2020

Biological Psychiatry

View full text Add to dashboard Cite

show abstract

“…As a G protein-coupled receptor (GPCR), the MOR also interacts with βarrestins, scaffolding proteins that serve to regulate or facilitate subsequent GPCR signaling. In studies spanning more than a decade, researchers have shown that the interaction between MOR and βarrestin2 may drive many of the unwanted side effects of MOR activation (Bohn et al, 2000; Bohn et al, 1999; Bu et al, 2015; Li et al, 2009; Raehal, 2011; Raehal and Bohn, 2005). βArrestin2-KO mice, for example, display enhanced and prolonged morphine-induced antinociception yet are protected from morphine-induced respiratory suppression (Bohn et al, 1999; Raehal et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics

Schmid

Kennedy

Ross

et al. 2017

Cell

424

545

View full text Add to dashboard Cite

SUMMARY Biased agonism has been proposed as a means to separate desirable and adverse drug responses downstream of G protein-coupled receptor (GPCR) targets. Herein we describe structural features of a series of mu opioid receptor (MOR)-selective agonists that preferentially activate receptor to couple to G proteins or to recruit βarrestin proteins. By comparing relative bias for MOR-mediated signaling in each pathway, we demonstrate a strong correlation between the respiratory suppression/antinociception therapeutic window in a series of compounds spanning a wide range of signaling bias. We find that βarrestin-biased compounds, such as fentanyl, are more likely to induce respiratory suppression at weak analgesic doses, while G protein signaling-bias broadens the therapeutic window, allowing for antinociception in the absence of respiratory suppression.

show abstract

“…Further, the knockdown or deletion of barrestin2 has been shown to attenuate morphine tolerance in rodent models (Bu et al, 2015;Li et al, 2009;Yang et al, 2011). We found that while barrestin2knockout (KO) mice did not become tolerant in the hot plate test, they did become tolerant in the warm water tail immersion assay (Bohn et al, 2002).…”

Section: Introductionmentioning

confidence: 87%

Comparison of morphine, oxycodone and the biased MOR agonist SR-17018 for tolerance and efficacy in mouse models of pain

Pantouli¹,

Grim²,

Schmid³

et al. 2020

Preprint

View full text Add to dashboard Cite

The mu opioid receptor-selective agonist, SR-17018, preferentially activates GTPS binding over beta-arrestin2 recruitment in cellular assays. In mice, SR-17018 stimulates GTPgammaS binding in brainstem and produces antinociception with potencies similar to morphine. However, it produces much less respiratory suppression and mice do not develop antinociceptive tolerance in the hot plate assay upon repeated dosing. Herein we evaluate the effects of acute and repeated dosing of SR-17018, oxycodone and morphine in additional models of pain-related behaviors. In the mouse warm water tail immersion assay, an assessment of spinal reflex to thermal nociception, repeated administration of SR-17018 produces tolerance as does morphine and oxycodone. SR-17018 retains efficacy in a formalin-induced inflammatory pain model upon repeated dosing, while oxycodone does not. In a chemotherapeutic-induced neuropathy pain model SR-17018 is more potent and efficacious than morphine or oxycodone, moreover, this efficacy is retained upon repeated dosing of SR-17018. These findings demonstrate that, with the exception of the tail flick test, SR-17018 retains efficacy upon chronic treatment across several pain models.

show abstract

Enhancement of morphine analgesia and prevention of morphine tolerance by downregulation of β-arrestin 2 with antigene RNAs in mice

Cited by 24 publications

References 33 publications

Toward Directing Opioid Receptor Signaling to Refine Opioid Therapeutics

Toward Directing Opioid Receptor Signaling to Refine Opioid Therapeutics

Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics

Comparison of morphine, oxycodone and the biased MOR agonist SR-17018 for tolerance and efficacy in mouse models of pain

Contact Info

Product

Resources

About