Arresting the Development of Addiction: The Role of<i>β</i>-Arrestin 2 in Drug Abuse

Porter-Stransky, Kirsten A.

doi:10.1124/jpet.117.240622

Cited by 38 publications

(32 citation statements)

References 84 publications

(128 reference statements)

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“…Our results showed that pro-inflammatory cytokines from RAW264.7 cells obviously increased at 6 h after treatment with LPS, which revealed that RAW264.7 could act as Kupffer cells when stimulated by LPS. It is well known that β-arrestin 2 is involved in various cell signaling pathways and plays a key role in the regulation of cell signaling[ 23 ]. For example, β-arrestin 2 acts as a scaffold protein and participates in the activation of JNK and ERK in the MAPK pathway[ 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

β-arrestin 2 attenuates lipopolysaccharide-induced liver injuryviainhibition of TLR4/NF-κB signaling pathway-mediated inflammation in mice

Jiang¹,

Xu²,

Guo³

et al. 2018

WJG

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AIMTo study the role and the possible mechanism of β-arrestin 2 in lipopolysaccharide (LPS)-induced liver injury in vivo and in vitro.METHODSMale β-arrestin 2+/+ and β-arrestin 2-/- C57BL/6J mice were used for in vivo experiments, and the mouse macrophage cell line RAW264.7 was used for in vitro experiments. The animal model was established via intraperitoneal injection of LPS or physiological sodium chloride solution. Blood samples and liver tissues were collected to analyze liver injury and levels of pro-inflammatory cytokines. Cultured cell extracts were collected to analyze the production of pro-inflammatory cytokines and expression of key molecules involved in the TLR4/NF-κB signaling pathway.RESULTSCompared with wild-type mice, the β-arrestin 2 knockout mice displayed more severe LPS-induced liver injury and significantly higher levels of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-10. Compared with the control group, pro-inflammatory cytokines (including IL-1β, IL-6, TNF-α, and IL-10) produced by RAW264.7 cells in the β-arrestin 2 siRNA group were significantly increased at 6 h after treatment with LPS. Further, key molecules involved in the TLR4/NF-κB signaling pathway, including phospho-IκBα and phosho-p65, were upregulated.CONCLUSIONβ-arrestin 2 can protect liver tissue from LPS-induced injury via inhibition of TLR4/NF-κB signaling pathway-mediated inflammation.

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Section: Discussionmentioning

confidence: 99%

β-arrestin 2 attenuates lipopolysaccharide-induced liver injuryviainhibition of TLR4/NF-κB signaling pathway-mediated inflammation in mice

Jiang¹,

Xu²,

Guo³

et al. 2018

WJG

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“…Beta-arrestin 2 (βarr2) plays a central role in the rewarding profiles of morphine, cocaine and alcohol [ 1 – 4 ]. In contrast, very little is known of the role of Beta-arrestin 1 (βarr1) in reward-motivated learning and behavior [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Beta-arrestin 1 regulation of reward-motivated behaviors and glutamatergic function

et al. 2017

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The two highly homologous non-visual arrestins, beta-arrestin 1 and 2, are ubiquitously expressed in the central nervous system, yet knowledge of their disparate roles is limited. While beta-arrestin 2 (βarr2) has been implicated in several aspects of reward-related learning and behavior, very little is known about the behavioral function of beta-arrestin 1 (βarr1). Using mice lacking βarr1, we focused on the role of this scaffolding and signal transduction protein in reward-motivated behaviors and in striatal glutamatergic function. We found that βarr1 KO mice were both slower in acquiring cocaine self-administration and in extinguishing this behavior. They also showed deficits in learning tasks supported by a natural food reward, suggesting a general alteration in reward processing. We then examined glutamatergic synaptic strength in WT and KO medium spiny neurons (MSNs) of the Nucleus Accumbens (NAc) shell in naïve animals, and from those that underwent cocaine self-administration. An increase in the AMPA/NMDA (A/N) ratio and a relative lack of GluN2B-enriched NMDARs was found in naïve KO vs WT MSNs. Applying Lim Domain Kinase (LIMK1), the kinase that phosphorylates and inactivates cofilin, to these cells, showed that both βarr1 and LIMK regulate the A/N ratio and GluN2B-NMDARs. Cocaine self-administration increased the A/N ratio and GluN2B-NMDARs in WT MSNs and, although the A/N ratio also increased in KO MSNs, this was accompanied by fewer GluN2B-NMDARs and an appearance of calcium-permeable AMPARs. Finally, to examine the consequences of reduced basal GluN2B-NMDARs in reward-processing seen in KO mice, we chronically infused ifenprodil, a GluN2B antagonist, into the NAc shell of WT mice. This intervention substantially reduced food-motivated behavior. Together these findings identify a previously unknown role of βarr1 in regulating specific reward-motivated behaviors and glutamatergic function.

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“…Opioid receptors are established drug targets for nonpeptide opioids such as morphine, fentanyl, or naloxone. These opioid receptor modulators are the most widely used analgesics in the clinic but their use is associated with severe drawbacks like tolerance, dependence, or respiratory depression, which were proposed to be linked to ligand and receptor bias towards arrestin recruitment [8][9][10] . Thus, a better understanding of opioid receptor signaling regulation and bias as well as new strategies to modulate opioid receptors with less adverse effects are not only timely but also urgently needed, especially considering the current opioid crisis.…”

mentioning

confidence: 99%

The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides

et al. 2020

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Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7, hitherto known as an atypical scavenger receptor for chemokines, is a broad-spectrum scavenger of opioid peptides. Phylogenetically, ACKR3 is intermediate between chemokine and opioid receptors and is present in various brain regions together with classical opioid receptors. Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. ACKR3 is not modulated by prescription opioids, but we show that an ACKR3-selective subnanomolar competitor peptide, LIH383, can restrain ACKR3's negative regulatory function on opioid peptides in rat brain and potentiate their activity towards classical receptors, which may open alternative therapeutic avenues for opioidrelated disorders. Altogether, our results reveal that ACKR3 is an atypical opioid receptor with cross-family ligand selectivity.

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Arresting the Development of Addiction: The Role ofβ-Arrestin 2 in Drug Abuse

Cited by 38 publications

References 84 publications

β-arrestin 2 attenuates lipopolysaccharide-induced liver injuryviainhibition of TLR4/NF-κB signaling pathway-mediated inflammation in mice

β-arrestin 2 attenuates lipopolysaccharide-induced liver injuryviainhibition of TLR4/NF-κB signaling pathway-mediated inflammation in mice

Beta-arrestin 1 regulation of reward-motivated behaviors and glutamatergic function

The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides

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