RB101‐mediated Protection of Endogenous Opioids: Potential Therapeutic Utility?

Jutkiewicz, Emily M.

doi:10.1111/j.1527-3458.2007.00011.x

Cited by 25 publications

(19 citation statements)

References 58 publications

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“…Although the anxiolytic properties of DOR selective agonists have been reported previously (Saitoh et al, 2004;Perrine et al, 2006;Jutkiewicz, 2007), the potential electrophysiological mechanisms by which these effects occur have yet to be investigated. Behaviorally, DOR knock-out mice display greater measures of anxiety than matched controls (Filliol et al, 2000), and selective ␦ antagonists can attenuate the anxiolytic actions of benzodiazepines (Primeaux et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

δ-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption

Margolis¹,

Fields²,

Hjelmstad³

et al. 2008

J. Neurosci.

106

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Alcoholism is a complex and debilitating syndrome affecting ϳ140 million people worldwide. However, not everyone who consumes ethanol develops abuse, raising the possibility that some individuals have a protective mechanism that inhibits elevated alcohol consumption. We tested the hypothesis that the ␦-opioid receptor (DOR) plays such a protective role. Here we show that DOR activity in the ventral tegmental area (VTA) robustly decreases ethanol consumption in rats and that these effects depend on baseline ethanol consumption. Intra-VTA microinjection of the DOR agonist DPDPE decreases drinking, particularly in low-drinking animals. Furthermore, VTA microinjection of the DOR selective antagonist TIPP-⌿ increases drinking in low, but not high, drinkers and this increase is blocked by comicroinjection of the GABA A antagonist bicuculline. Using electrophysiological techniques we found that in VTA brain slices from drinking rats DPDPE presynaptically inhibits GABA A receptor mediated IPSCs in low drinkers, but not in high drinkers or naive animals, most likely through activation of DORs on GABA terminals. This DOR-mediated inhibition of IPSCs also correlates inversely with behavioral correlates of anxiety measured in the elevated plus maze. In contrast, presynaptic inhibition of VTA GABA A IPSCs by theopioid receptor agonist DAMGO is significantly reduced in both high-and low-drinking rats (Ͻ30%) compared with age-matched nondrinking controls (Ͼ70%). Together, our findings demonstrate the protective nature of VTA DORs and identify an important new target for therapeutic intervention for alcoholism.

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Section: Discussionmentioning

confidence: 99%

δ-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption

Margolis¹,

Fields²,

Hjelmstad³

et al. 2008

J. Neurosci.

106

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“…DOR antinociception to thermal stimuli requires PLC and PKC activation also determines DOR-α2A synergistic effects in the spinal cord (140) . DOR agonists have been increasingly studied for their potential antidepressant and anxiolytic effects in rodent behavioral models (141) . However, it is not yet known how or where DOR agonists mediate antidepressant-like behavioral responses.…”

Section: Opioid Signaling and Behaviormentioning

confidence: 99%

Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior

2011

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Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years, and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled, and activate inhibitory G-proteins. These receptors form homo- and hetereodimeric complexes, signal to kinase cascades, and scaffold a variety of proteins. In this review, we discuss classical mechanisms and developments in understanding opioid tolerance, opioid receptor signaling, and highlight advances in opioid molecular pharmacology, behavioral pharmacology, and human genetics. We put into context how opioid receptor signaling leads to the modulation of behavior with the potential for therapeutic intervention. Finally, we conclude that there is a continued need for more translational work on opioid receptors in vivo.

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“…The same antagonists administered alone and at a higher dose produce anxiogenic effects (e.g., based on performance in an elevated-plus maze) (Perrine et al, 2006; Saitoh et al, 2004). DORs have further been implicated in normative anxiety regulation, most likely through the action of endogenous opioids (Jutkiewicz, 2007; Nieto et al, 2005). DORs also modulate the anxiolytic effects of the benzodiazepine diazepam.…”

Section: Introductionmentioning

confidence: 99%

Interaction between delta opioid receptors and benzodiazepines in CO2-induced respiratory responses in mice

Borkowski¹,

Barnes²,

Blanchette³

et al. 2011

Brain Research

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The false-suffocation hypothesis of panic disorder (Klein, 1993) suggested δ-opioid receptors as a possible source of the respiratory dysfunction manifested in panic attacks occurring in panic disorder (Preter and Klein, 2008). This study sought to determine if a lack of δ-opioid receptors in a mouse model affects respiratory response to elevated CO2, and whether the response is modulated by benzodiazepines, which are widely used to treat panic disorder. In a whole-body plethysmograph, respiratory responses to 5% CO2 were compared between δ-opioid receptor knockout mice and wild-type mice after saline, diazepam (1 mg/kg), and alprazolam (0.3 mg/kg) injection. The results show that lack of δ-opioid receptors does not affect normal response to elevated CO2, but does prevent benzodiazepines from modulating that response. Thus, in the presence of benzodiazepine agonists, respiratory responses to elevated CO2 were enhanced in δ-opioid receptor knockout mice compared to wild-type mice. This suggests an interplay between benzodiazepine receptors and δ-opioid receptors in regulating the respiratory effects of elevated CO2, which might be related to CO2 induced panic.

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RB101‐mediated Protection of Endogenous Opioids: Potential Therapeutic Utility?

Cited by 25 publications

References 58 publications

δ-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption

δ-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption

Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior

Interaction between delta opioid receptors and benzodiazepines in CO2-induced respiratory responses in mice

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