Regulators of G Protein Signaling in Analgesia and Addiction

Sakloth, Farhana; Polizu, Claire; Bertherat, Feodora; Zachariou, Venetia

doi:10.1124/mol.119.119206

Cited by 23 publications

(21 citation statements)

References 134 publications

(153 reference statements)

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“…Regulators of G-protein signaling (RGS) proteins bind to the activated G-α subunit of G-proteins, enhancing their GTPase activity and accelerating their return to the inactive G-α-GDP state, leading to signal termination . There are over 30 RGS proteins which include RGS9-2 and RGS4 that have been demonstrated to modulate the effects of opioids in an agonist-dependent manner .…”

Section: Combination Therapy With Opioidsmentioning

confidence: 99%

“…188 Thus, combination therapies of MOR and selective 5-HT 1A agonists should be further investigated because these cotherapies may decrease the proteins bind to the activated G-α subunit of G-proteins, enhancing their GTPase activity and accelerating their return to the inactive G-α-GDP state, leading to signal termination. 189 There are over 30 RGS proteins which include RGS9-2 and RGS4 that have been demonstrated to modulate the effects of opioids in an agonist-dependent manner. 87 In addition, downregulation of the RGS protein RGSz1 resulted in enhancement of analgesic efficacy and a reduction in the rewarding effects of opioids.…”

Section: Combination Therapy With Opioidsmentioning

confidence: 99%

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Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

et al. 2021

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Because of the problems associated with opioids, drug discovery efforts have been employed to develop opioids with reduced side effects using approaches such as biased opioid agonism, multifunctional opioids, and allosteric modulation of opioid receptors. Receptor targets such as adrenergic, cannabinoid, P2X3 and P2X7, NMDA, serotonin, and sigma, as well as ion channels like the voltage-gated sodium channels Nav1.7 and Nav1.8 have been targeted to develop novel analgesics. Several enzymes, such as soluble epoxide hydrolase, sepiapterin reductase, and MAGL/ FAAH, have also been targeted to develop novel analgesics. In this review, old and recent targets involved in pain signaling and compounds acting at these targets are summarized. In addition, strategies employed to reduce side effects, increase potency, and efficacy of opioids are also elaborated. This review should aid in propelling drug discovery efforts to discover novel analgesics.

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Section: Combination Therapy With Opioidsmentioning

confidence: 99%

Section: Combination Therapy With Opioidsmentioning

confidence: 99%

Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

et al. 2021

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“…MOR is widely distributed in the mesolimbic dopamine circuitry and is involved in the modulation of pain and addiction (Serafini et al, 2020). Many opioid receptorinteracting proteins regulate the signal transduction pathways of MOR that modulate the effects of opioids (Georgoussi et al, 2012;Sakloth et al, 2020). In our previous study, the MOR-interacting protein Hsp90β was shown to positively regulate MOR function, and the Hsp90β inhibitor decreased the tolerance and dependence induced by morphine (Zhang et al, 2020).…”

Section: Discussionmentioning

confidence: 95%

A20-Binding Inhibitor of Nuclear Factor-κB Targets β-Arrestin2 to Attenuate Opioid Tolerance

Zhang¹,

Zhou²,

Lu³

et al. 2021

Mol Pharmacol

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Opioids play an important role in pain relief, but repeated exposure results in tolerance and dependence. To make opioids more effective and useful, research in the field has focused on reducing the tolerance and dependence for chronic pain relief.Here, we showed the effect of ABIN-1 in modulating morphine function. We used hotplate tests and CPP tests to show that overexpression of ABIN-1 in the mice brain attenuated morphine dependence. These effects of ABIN-1 are most likely mediated through the formation of ABIN-1-β-arrestin2 complexes, which accelerate β-arrestin2 degradation by ubiquitination. With the degradation of β-arrestin2, ABIN-1 overexpression also decreased MOR phosphorylation and internalization following opioid treatment, affecting the β-arrestin2-dependent signaling pathway to regulate morphine tolerance. Importantly, the effect of ABIN-1 on morphine tolerance was abolished in β-arrestin2 knockout mice. Taken together, these results suggest that the interaction between ABIN-1 and β-arrestin2 inhibits MOR internalization to attenuate morphine tolerance, revealing a novel mechanism for MOR regulation. Hence, ABIN-1 may be a therapeutic target to regulate MOR internalization, thus providing a foundation for a novel treatment strategy for alleviating morphine tolerance and dependence.

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“…Behavioral and cellular effects of psychostimulants are modulated in part by regulators of G-protein signaling (RGS) proteins (Hooks et al 2008; Sakloth et al 2020). RGS proteins are characterized by an RGS domain that facilitates the termination of G-protein coupled receptor (GPCR) signaling by enhancing the GTPase activity of Ga subunits, limiting the duration of downstream signaling events (Ross and Wilkie 2000).…”

Section: Introductionmentioning

confidence: 99%

RGS14 modulates locomotor behavior and ERK signaling induced by environmental novelty and cocaine within discrete limbic structures

Foster

Lustberg

Harbin

et al. 2021

Preprint

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RationaleIn rodents, exposure to novel environments or psychostimulants promotes locomotor activity. Indeed, locomotor reactivity to novelty strongly predicts behavioral responses to psychostimulants in animal models of addiction. RGS14 is a plasticity restricting protein with unique functional domains that enable it to suppress ERK-dependent signaling as well as regulate G protein activity. Although recent studies show that RGS14 is expressed in multiple limbic regions implicated in psychostimulant- and novelty-induced hyperlocomotion, its function has been studied almost entirely in the context of hippocampal physiology and hippocampusdependent behaviors.ObjectiveWe sought to determine whether RGS14 modulates novelty- and psychostimulant-induced locomotion and neuronal activity.MethodsWe assessed Rgs14 knockout (RGS14 KO) mice and wild-type (WT) littermate controls using novelty-induced locomotion (NIL) and cocaine-induced locomotion (CIL) behavioral tests with subsequent quantification of c-fos and phosphorylated ERK (pERK) induction in limbic regions that express RGS14.ResultsCompared to WT controls, RGS14 KO mice exhibited attenuated locomotor responses in the NIL test, driven by avoidance of the center of the novel environment. By contrast, RGS14 KO mice demonstrated augmented peripheral locomotion in the CIL test conducted in either a familiar or novel environment. The absence of RGS14 enhanced induction of c-fos and pERK in the central amygdala and hippocampus (areas CA1 and CA2) when cocaine was administered in a novel environment.ConclusionsRGS14 regulates novelty- and psychostimulant-induced hyperlocomotion, particularly with respect to thigmotaxis. Further, our findings suggest RGS14 may reduce neuronal activity in discrete limbic subregions by inhibiting ERK-dependent signaling and transcription.

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Regulators of G Protein Signaling in Analgesia and Addiction

Cited by 23 publications

References 134 publications

Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

A20-Binding Inhibitor of Nuclear Factor-κB Targets β-Arrestin2 to Attenuate Opioid Tolerance

RGS14 modulates locomotor behavior and ERK signaling induced by environmental novelty and cocaine within discrete limbic structures

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