Antinociceptive potentiation and attenuation of tolerance by intrathecal β-arrestin 2 small interfering RNA in rats

Yang, Chao‐Hsun; Huang, Hui; Chen, K.-H.; Chen, Y.-S.; Sheen-Chen, Shyr Ming; Lin, Chung Ren

doi:10.1093/bja/aer291

Cited by 61 publications

(51 citation statements)

References 33 publications

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“…In b-arrestin-2 KO mice, morphine analgesia was enhanced and prolonged, with reduced desensitization, compared with morphine in wild type littermates (Bohn et al, 1999). Similar findings were noted in both mice and rats following injection of b-arrestin-2 interfering RNAs to specific brain regions (Li et al, 2009;Yang et al, 2011). In contrast, morphine-induced constipation and respiratory suppression were reduced in b-arrestin-2 KO mice versus wild type animals (Raehal et al, 2005).…”

Section: Introductionsupporting

confidence: 55%

A G Protein-Biased Ligand at theμ-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphine

DeWire¹,

Yamashita²,

Rominger³

et al. 2013

J Pharmacol Exp Ther

533

578

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The concept of ligand bias at G protein-coupled receptors broadens the possibilities for agonist activities and provides the opportunity to develop safer, more selective therapeutics. Morphine pharmacology in b-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the m-opioid receptor (MOR) to G proteins, but not b-arrestins, would result in higher analgesic efficacy, less gastrointestinal dysfunction, and less respiratory suppression than morphine. Here we report the discovery of TRV130 ([(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine), a novel MOR G protein-biased ligand. In cell-based assays, TRV130 elicits robust G protein signaling, with potency and efficacy similar to morphine, but with far less b-arrestin recruitment and receptor internalization. In mice and rats, TRV130 is potently analgesic while causing less gastrointestinal dysfunction and respiratory suppression than morphine at equianalgesic doses. TRV130 successfully translates evidence that analgesic and adverse MOR signaling pathways are distinct into a biased ligand with differentiated pharmacology. These preclinical data suggest that TRV130 may be a safer and more tolerable therapeutic for treating severe pain.

show abstract

Section: Introductionsupporting

confidence: 55%

A G Protein-Biased Ligand at theμ-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphine

DeWire¹,

Yamashita²,

Rominger³

et al. 2013

J Pharmacol Exp Ther

533

578

View full text Add to dashboard Cite

show abstract

“…As adverse effects have been associated with β-arrestin2 recruitment, 39−50 we investigated how 3 would affect such recruitment upon activation in the presence of singly expressing or coexpressing opioid receptors in HEK293 cells. Similar experiments also were carried out with standard μ, δ, and κ agonist ligands (DAMGO, 51 DPDPE, 52 U69593, 53 respectively) as controls.…”

Section: Biological Resultsmentioning

confidence: 99%

“…8−15 As this network has been considered to be a source of some adverse effects, it has been proposed that a viable approach to the development of drugs with fewer side effects can be accomplished by reducing, modifying, or preventing interaction of β-arrestin with the GPCR. 39,40,42,43,45,46,56−58 …”

Section: Discussionmentioning

confidence: 99%

Putative Kappa Opioid Heteromers As Targets for Developing Analgesics Free of Adverse Effects

et al. 2014

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It is now generally recognized that upon activation by an agonist, β-arrestin associates with G protein-coupled receptors and acts as a scaffold in creating a diverse signaling network that could lead to adverse effects. As an approach to reducing side effects associated with κ opioid agonists, a series of β-naltrexamides 3–10 was synthesized in an effort to selectively target putative κ opioid heteromers without recruiting β-arrestin upon activation. The most potent derivative 3 (INTA) strongly activated KOR-DOR and KOR-MOR heteromers in HEK293 cells. In vivo studies revealed 3 to produce potent antinociception, which, when taken together with antagonism data, was consistent with the activation of both heteromers. 3 was devoid of tolerance, dependence, and showed no aversive effect in the conditioned place preference assay. As immunofluorescence studies indicated no recruitment of β-arrestin2 to membranes in coexpressed KOR-DOR cells, this study suggests that targeting of specific putative heteromers has the potential to identify leads for analgesics devoid of adverse effects.

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“…siRNA inhibition of β-arrestin2 in the periaqueductal gray of mice enhances acute morphine-induced antinociception and delays the development of antinociceptive tolerance in the hot plate test (Li et al 2009). Morphine-induced antinociceptive tolerance in the tail flick test has also been shown to be significantly reduced in rats in which β-arrestin2 expression is knocked down in the spinal cord (Przewlocka et al 2002; Yang et al 2011). Moreover, the antinociceptive effects of morphine in the hot plate test are absent in rats overexpressing β-arrestin2 in the periaqueductal gray (Jiang et al 2006).…”

Section: β-Arrestin Regulation Of Mor- and Cb1r-mediated Antinocicementioning

confidence: 99%

β-Arrestins: Regulatory Role and Therapeutic Potential in Opioid and Cannabinoid Receptor-Mediated Analgesia

Raehal

Bohn

2013

Handbook of Experimental Pharmacology

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Pain is a complex disorder with neurochemical and psychological components contributing to the severity, the persistence, and the difficulty in adequately treating the condition. Opioid and cannabinoids are two classes of analgesics that have been used to treat pain for centuries and are arguably the oldest of “pharmacological” interventions used by man. Unfortunately, they also produce several adverse side effects that can complicate pain management. Opioids and cannabinoids act at G protein-coupled receptors (GPCRs), and much of their effects are mediated by the mu-opioid receptor (MOR) and cannabinoid CB1 receptor (CB1R), respectively. These receptors couple to intracellular second messengers and regulatory proteins to impart their biological effects. In this chapter, we review the role of the intracellular regulatory proteins, β-arrestins, in modulating MOR and CB1R and how they influence the analgesic and side-effect profiles of opioid and cannabinoid drugs in vivo. This review of the literature suggests that the development of opioid and cannabinoid agonists that bias MOR and CB1R toward G protein signaling cascades and away from β-arrestin interactions may provide a novel mechanism by which to produce analgesia with less severe adverse effects.

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Antinociceptive potentiation and attenuation of tolerance by intrathecal β-arrestin 2 small interfering RNA in rats

Abstract: We show here that intrathecal β-arrestin 2 siRNA in rats enhances analgesia and attenuates naloxone-induced withdrawal symptoms. This may warrant further investigation in the context of long-term use of intrathecal opioids for controlling chronic pain.

Cited by 61 publications

References 33 publications

A G Protein-Biased Ligand at theμ-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphine

A G Protein-Biased Ligand at theμ-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphine

Putative Kappa Opioid Heteromers As Targets for Developing Analgesics Free of Adverse Effects

β-Arrestins: Regulatory Role and Therapeutic Potential in Opioid and Cannabinoid Receptor-Mediated Analgesia

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