Long-Acting κ Opioid Antagonists Disrupt Receptor Signaling And Produce Noncompetitive Effects By Activating C-Jun N-Terminal Kinase

Bruchas, Michael R.; Yang, Tao; Schreiber, Selena; DeFino, Mia C.; Kwan, Steven C.; Li, Shuang; Chavkin, Charles

doi:10.1074/jbc.m705540200

Cited by 170 publications

(248 citation statements)

References 39 publications

(60 reference statements)

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“…We suspected that the serotonergic system might be involved in mediating aversive effects of kappa agonists because of the known effects of this system in regulating mood. The principal source of serotonin in the mammalian brain is the DRN (14,15), and to assess its role, we first used local injection of the long-acting antagonist norBNI that stably inactivates KOR signaling; the antagonist effects of norBNI were previously shown to last more than 3 weeks in mice (19,20), a duration sufficient for these behavioral experiments. Local norBNI injection into the DRN significantly blocked CPA caused by administration of U50,488 ( Fig.…”

Section: Kappa-opioid Receptors In the Drn Mediate Aversion And Drugmentioning

confidence: 99%

Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking

Land

Bruchas²,

Schattauer³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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267

285

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Although stress has profound effects on motivated behavior, the underlying mechanisms responsible are incompletely understood. In this study we elucidate a functional pathway in mouse brain that encodes the aversive effects of stress and mediates stress-induced reinstatement of cocaine place preference (CPP). Activation of the dynorphin/kappa opioid receptor (KOR) system by either repeated stress or agonist produces conditioned place aversion (CPA). Because KOR inhibition of dopamine release in the mesolimbic pathway has been proposed to mediate the dysphoria underlying this response, we tested dopamine-deficient mice in this study and found that KOR agonist in these mice still produced CPA. However, inactivation of serotonergic KORs by injection of the KOR antagonist norBNI into the dorsal raphe nucleus (DRN), blocked aversive responses to the KOR agonist U50,488 and blocked stress-induced reinstatement of CPP. KOR knockout (KO) mice did not develop CPA to U50,488; however, lentiviral re-expression of KOR in the DRN of KOR KO mice restored place aversion. In contrast, lentiviral expression in DRN of a mutated form of KOR that fails to activate p38 MAPK required for KORdependent aversion, did not restore place aversion. DRN serotonergic neurons project broadly throughout the brain, but the inactivation of KOR in the nucleus accumbens (NAc) coupled with viral re-expression in the DRN of KOR KO mice demonstrated that aversion was encoded by a DRN to NAc projection. These results suggest that the adverse effects of stress may converge on the serotonergic system and offers an approach to controlling stress-induced dysphoria and relapse.depression ͉ drug addiction ͉ dynorphin ͉ serotonin S tress has profound effects on human health and can lead to mood disorders including clinical depression, anxiety, and can increase comorbid drug addiction risk (1-3). Corticotropin releasing factor (CRF) orchestrates the complex endocrine and neuronal responses to behavioral stress exposure (4), and recent studies have suggested that the dysphoric properties of stress are encoded by CRF-induced activation of the endogenous dynorphin opioid system (5). Systemic administration of kappa opioid receptor (KOR) antagonists block the aversive (5) and pro-addictive effects of stress (6-9), and dynorphin activation of KOR is thought to mediate opponent processes evoked by addictive drugs (10), yet the key sites of dynorphin/KOR action mediating these behavioral responses are not resolved.Mice subjected to behavioral stress show dynorphin release and robust KOR activation in both dopaminergic and serotonergic nuclei (5), implying that these neurotransmitters could be important for KOR-dependent stress-induced behavioral responses. Ventral tegmental area (VTA) dopaminergic projections to the nucleus accumbens (NAc) have been linked to addiction (11), making this an obvious target for the regulation of appetitive and aversive behaviors. However, prior studies have shown that mice lacking dopamine can still develop place preference for drugs of...

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Section: Kappa-opioid Receptors In the Drn Mediate Aversion And Drugmentioning

confidence: 99%

Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking

Land

Bruchas²,

Schattauer³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

267

285

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“…A 4-day experimental design was used in experiments with the k-opioid antagonist norbinaltorphimine (norBNI) to accommodate its slow onset and long duration of action (Bruchas et al, 2007;Endoh et al, 1992), and two groups of rats were used to examine the effects of norBNI pretreatment on the effects of i.p. acid and U69593, respectively.…”

Section: Assay Of Microdialysismentioning

confidence: 99%

Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

Leitl

Onvani

Bowers

et al. 2013

Neuropsychopharmacol

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Pain is often associated with depression of behavior and mood, and relief of pain-related depression is a common goal of treatment. This study tested the hypothesis that pain-related behavioral depression is mediated by activation of endogenous k-opioid systems and subsequent depression of mesolimbic dopamine release. Adult male Sprague-Dawley rats were implanted with electrodes targeting the medial forebrain bundle (for behavior studies of intracranial self-stimulation (ICSS)) or with cannulae for microdialysis measures of nucleus accumbens dopamine (NAc DA). Changes in ICSS and NAc DA were examined after treatment with a visceral noxious stimulus (intraperitoneal injection of dilute lactic acid) or an exogenous k-agonist (U69593). Additional studies examined the sensitivity of acid and U69593 effects to blockade by two analgesics (the nonsteroidal antiinflammatory drug ketoprofen and the m-opioid agonist morphine) or by the k-antagonist norbinaltorphimine (norBNI). The effects of acid were also examined on mRNA expression for prodynorphin (PDYN) and k-opioid receptors (KORs) in mesocorticolimbic brain regions. Both acid and U69593 depressed ICSS and extracellular levels of NAc DA. Pain-related acid effects were blocked by ketoprofen and morphine but not by norBNI. The U69593 effects were blocked by norBNI but not by ketoprofen, and were only attenuated by morphine. Acid did not significantly alter PDYN or KOR in NAc, but it produced a delayed increase in PDYN in prefrontal cortex. These results support a key role for the mesolimbic DA system, but a more nuanced role for endogenous k-opioid systems, in mediating acute pain-related behavioral depression in rats.

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“…The data also show that agonist binding to KOR is important for EGF-stimulated neurite/axon extension. Activation of opioid receptor, including KOR, by agonists is known to modulate multiple down stream signaling effectors that are potential axon outgrowth regulators, such as extracellular signal-regulated kinase 1/2 (ERK1/2) (34), p38 mitogen-activated protein kinase (MAPK) (35), and c-Jun N-terminal kinase (JNK) (36). Whether and how these effectors contribute specifically to EGF-stimulated neurite outgrowth needs to be evaluated in the future.…”

Section: Signal Of Egf To Stimulate Kor/dynorphin-dependent Axon Extementioning

confidence: 99%

Kappa opioid receptor contributes to EGF-stimulated neurite extension in development

Tsai

Tsui

Pintar

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Epidermal growth factor (EGF), a mitogen, also stimulates neurite extension during development, but the underlying mechanism is elusive. This study reveals a functional role for kappa opioid receptor (KOR) in EGF-stimulated neurite extension, and the underlying mechanism. EGF and activated EGF receptor (EGFR) levels are elevated in embryonic spinal cords during late gestation stages, with concurrent rise in protein levels of KOR and axon extension markers, growth-associated protein 43 (GAP43), and transient axonal glycoprotein-1 (TAG-1). Both GAP43 and TAG-1 levels are significantly lower in KOR-null (KOR −/− ) spinal cords, and EGFR inhibitors effectively reduce the levels of KOR, GAP43, and TAG-1 in wildtype embryonic spinal cords. For KOR −/− or KOR-knockdown dorsal root ganglion (DRG) neurons, EGF can no longer effectively stimulate axon extension, which can be rescued by introducing a constitutive KOR expressing vector but not by a regulated KOR vector carrying its 5′ untranslated region, which can be bound and repressed by growth factor receptor-bound protein 7 (Grb7). Furthermore, blocking KOR activation by application of anti-dynorphin, KOR antagonist, or EGFR inhibitor effectively reduces axon extension of DRG neurons. Thus, EGF-stimulated axon extension during development is mediated, at least partially, by specific elevation of KOR protein production at posttranscriptional level, as well as activation of KOR signaling. The result also reveals an action of EGF to augment posttranscriptional regulation of certain mRNAs during developmental stages.5′ untranslated region | dorsal root ganglion | epidermal growth factor | growth factor receptor-bound protein 7 | posttranscriptional regulation

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Long-Acting κ Opioid Antagonists Disrupt Receptor Signaling And Produce Noncompetitive Effects By Activating C-Jun N-Terminal Kinase

Cited by 170 publications

References 39 publications

Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking

Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking

Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

Kappa opioid receptor contributes to EGF-stimulated neurite extension in development

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