β‐Arrestin 2 dependence of δ opioid receptor agonists is correlated with alcohol intake

Abstract

BACKGROUND AND PURPOSEδ Opioid receptor agonists are being developed as potential treatments for depression and alcohol use disorders. This is particularly interesting as depression is frequently co-morbid with alcohol use disorders. Yet we have previously shown that δ receptor agonists range widely in their ability to modulate alcohol intake; certain δ receptor agonists actually increase alcohol consumption in mice. We propose that variations in β-arrestin 2 recruitment contribute to the differential behavioural profile of δ receptor agonists. EXPERIMENTAL APPROACHWe used three diarylmethylpiperazine-based non-peptidic δ receptor selective agonists (SNC80, SNC162 and ARM390) and three structurally diverse δ receptor agonists (TAN-67, KNT127 and NIH11082). We tested these agonists in cAMP and β-arrestin 2 recruitment assays and a behavioural assay of alcohol intake in male C57BL/6 mice. We used β-arrestin 2 knockout mice and a model of depression-like behaviour to further study the role of β-arrestin 2 in δ receptor pharmacology. KEY RESULTSAll six tested δ receptor agonists were full agonists in the cAMP assay but displayed distinct β-arrestin 2 recruitment efficacy. The efficacy of δ receptor agonists to recruit β-arrestin 2 positively correlated with their ability to increase alcohol intake (P < 0.01). The effects of the very efficacious recruiter SNC80 on alcohol intake, alcohol place preference and depression-like behaviour were β-arrestin 2-dependent. CONCLUSIONS AND IMPLICATIONSOur finding that δ receptor agonists that strongly recruit β-arrestin 2 can increase alcohol intake carries important ramifications for drug development of δ receptor agonists for treatment of alcohol use disorders and depressive disorders.

Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57BL/6 mice

“…Besides a role in antinociception, DORs are implicated in alcohol consumption, depression and anxiety including alcohol withdrawal-induced anxiety (Filliol et al, 2000; Saitoh et al, 2004; van Rijn et al, 2010; Vergura et al, 2008). We and others have shown in preclinal animal models that the DOR-selective agonist TAN-67 can produce analgesia and reduce alcohol intake, depression and anxiety (Chiang et al, 2016; Kamei et al, 1995; van Rijn et al, 2010; van Rijn and Whistler, 2009). Hence, we were interested in investigating whether TAN-67, specifically, would alleviate AWiMA.…”

“…TAN-67 has frequently been labeled as a DOR1-selective agonist. The pharmacology underlying the subtypes is not well defined, but our data suggests that TAN-67 may interact with DOR-mu opioid receptor heteromers (van Rijn and Whistler, 2009) and have strong G-protein signaling bias, with limited efficacy for β-arrestin2 recruitment (Chiang et al, 2016). While our data would support DORs as a drug target for prevention but not treatment of AWiMA, it is important to consider that DOR agonists alleviate other components of the alcohol withdrawal syndrome.…”

“…While our data would support DORs as a drug target for prevention but not treatment of AWiMA, it is important to consider that DOR agonists alleviate other components of the alcohol withdrawal syndrome. Also, different DOR agonists with an intermediate β-arrestin2 recruitment efficacy such as KNT-127 (Chiang et al, 2016; Nagase et al, 2010; Nozaki et al, 2014; Saitoh et al, 2011) may be more capable of reducing alcohol withdrawal induced hyperalgesia.…”

The role of regulator of G protein signaling 4 in delta-opioid receptor-mediated behaviors

“…Alternatively, these specific DOPr-mediated behaviors may be generated by a G protein-independent, arrestin-mediated signaling mechanism (Violin 2014). Previous studies demonstrated that DOPr activation leads to signaling through G protein-dependent and - independent pathways (Bradbury et al 2009; Charfi et al 2014; Charfi et al 2015); however, there are few reports connecting these distinct signaling mechanisms to specific behavioral outputs (Chiang et al 2016; Pradhan et al 2016). In conclusion, this study demonstrates that RGS4 differentially regulates SNC80-induced behaviors, suggesting that different molecular or cellular signaling pathways or neurocircuitry mediate these behavioral outcomes.…”

The Meta-Position of Phe4 in Leu-enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

“…[12][13][14] As such, relatively few studies have systematically assessed this alternate pathway despite its important roles in regulating OR desensitization, and purported promotion of β-arrestin-dependent signal transduction through the scaffolding of various kinases. 15 An increasing number of studies have implicated δOR mediated β-arrestin recruitment with various (patho)physiological effects, ranging from tolerance, 16 alcohol intake 17,18 and δOR agonist-induced seizures. 16 To minimize these adverse effects, the development of "biased" ligands that can selectively activate the G protein pathway, without engaging the β-arrestinassociated pathways, 19 may provide a key set of pharmacological tools for reevaluating the drugability of δOR for several disease states.…”