The role of the dynorphin–κ opioid system in the reinforcing effects of drugs of abuse

Wee, Sunmee; Koob, George F.

doi:10.1007/s00213-010-1825-8

Cited by 359 publications

(357 citation statements)

References 159 publications

(184 reference statements)

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“…KOR activation in DA neuronal cells affects the state of the brain reward system and behavior by regulating neuronal activity. 28 However, the high level of KOR in adjacent non-neuronal cells, particularly in immune-derived microglia such as those in the SN associated with neurodegeneration in PD, has raised the question of whether it has a regulatory role in inflammatory microglial exacerbation of neurodegenerative disorders. To define what cell types are responsible for endotoxin-mediated neurotoxicity in wild-type (WT) versus KOR knockout (Kor À / À ) animals, we explored the in vitro effects of LPS-treated microglia and astrocytes derived from WT or Kor À / À mice on SN-derived TH þ neurons from both WT and Kor À / À mice.…”

Section: Resultsmentioning

confidence: 99%

β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia

Feng

Burton

et al. 2013

Cell Death Differ

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Microglial activation worsens neuronal loss and contributes to progressive neurological diseases like Parkinson's disease (PD). This inflammatory progression is countered by dynorphin (Dyn), the endogenous ligand of the kappa-opioid receptor (KOR). We show that microglial b-arrestin mediates the ability of Dyn/KOR to limit endotoxin-elicited production of pro-inflammatory effectors and cytokines, subsequently protecting neurons from inflammation-induced neurotoxicity. Agonist-activated KOR enhances the interaction of b-arrestin2 with transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1), disrupting TAK1-TAB1 mediated pro-inflammatory gene expression. We reveal a new physiological role for b-arrestin in neuroprotection via receptor internalization-triggered blockade of signal effectors of microglial inflammatory neurotoxicity. This result offers novel drug targets in the convergent KOR/b-arrestin2 and inflammatory pathways for treating microglial inflammatory neuropathologies like PD. Cell Death and Differentiation (2014) 21, 397-406; doi:10.1038/cdd.2013 published online 25 October 2013 Increasing evidence suggests that the overactivation of immune system-derived microglia in the substantia nigra (SN) is a key causative factor in the pathogenesis of Parkinson's disease (PD), the most prevalent neurodegenerative disease in the population over 60 years old. Pathologically, PD is characterized by the degeneration of dopaminergic (DA) neurons of the SN pars compacta (SNpc) in the midbrain, leading to disabled voluntary movements. Immunohistochemistry research has indicated that activated microglia accumulate around degenerating neurons in the SN of patients with PD and related parkinsonian syndromes. 1 Although microglial activation in these diseases is not limited to the SN, the DA neurons in the SN are particularly vulnerable to inflammatory insult owing to the larger population of microglia in the SN. 2,3 As a sensor of brain injury and aging, microglia's state and activity are regulated through neuronmicroglia communication involving the stimulation of signal transducing or phagocytic microglial receptors by neurotransmitters. 4,5 Deficiencies in this communication between neurons and microglia as a result of stress or aging leads to reactive microglia and prolonged inflammation and, as a result, neuronal death. Similarly, stimulation of microglia by bacteria or endotoxins results in outbursts of pro-inflammatory cytokines such as interleukin 1 beta (IL-1b), tumor necrosis factor-a (TNF)-a, and interleukin 6 (IL-6) through activation of toll-like receptor 4 (TLR4). This can contribute to the death of neurons in the SN because long-term inhibition of IL-1b and TNF-a has consistently been reported to attenuate tyrosine hydroxylase (TH þ ) neuron loss in PD models. 6,7 Meanwhile, neuron degeneration itself leads to further secondary activation of microglia via increased production of matrix metalloproteinase 3 and neuromelaine and, as a result, further neuronal death. [8][9][10] Thus...

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Section: Resultsmentioning

confidence: 99%

β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia

Feng

Burton

et al. 2013

Cell Death Differ

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“…It has been postulated that this hypodopaminergic state contributes to the emotional/motivational component of ethanol dependence, although activation of other neurotransmitter systems, such as those involving corticotropin-releasing factor or the endogenous k-opioid dynorphin, has also been implicated (Koob, 2009;Wee and Koob, 2010). In support of the role of the hypodopaminergic state in dependence, ethanolwithdrawn animals have been shown to self-administer ethanol until NAc dopamine levels are restored to the prewithdrawal baseline levels (Weiss et al, 1996).…”

Section: Enhanced D 2 Autoinhibition and Hypodopaminergic State Durinmentioning

confidence: 99%

In Vivo Ethanol Experience Increases D2 Autoinhibition in the Ventral Tegmental Area

Perra

Clements

Bernier

et al. 2011

Neuropsychopharmacol

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Alcoholism is characterized by compulsive alcohol intake after a history of chronic consumption. A reduction in mesolimbic dopaminergic transmission observed during abstinence may contribute to the negative affective state that drives compulsive intake. Although previous in vivo recording studies in rodents have demonstrated profound decreases in the firing activity of ventral tegmental area (VTA) dopamine neurons after withdrawal from long-term ethanol exposure, the cellular mechanisms underlying this reduced activity are not well understood. Somatodendritic dopamine release within the VTA exerts powerful feedback inhibition of dopamine neuron activity via stimulation of D 2 autoreceptors and subsequent activation of G protein-gated inwardly rectifying K + (GIRK) channels. Here, by performing patch-clamp recordings from putative dopamine neurons in the VTA of mouse brain slices, we show that D 2 receptor/ GIRK-mediated inhibition becomes more potent and exhibits less desensitization after withdrawal from repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 days). In contrast, GABA B receptor/GIRK-mediated inhibition and its desensitization are not affected. Chelating cytosolic Ca 2 + with BAPTA augments D 2 inhibition and suppresses its desensitization in control mice, while these effects of BAPTA are occluded in ethanol-treated mice. Furthermore, inositol 1,4,5-trisphosphate (IP 3 )-induced intracellular Ca 2 + release and Ca 2 + /calmodulin-dependent protein kinase II are selectively involved in the desensitization of D 2 , but not GABA B , receptor signaling. Consistent with this, activation of metabotropic glutamate receptors that are coupled to IP 3 generation leads to cross-desensitization of D 2 /GIRK-mediated responses. We propose that enhancement of D 2 receptor-mediated autoinhibition via attenuation of a Ca 2 + -dependent desensitization mechanism may contribute to the hypodopaminergic state during ethanol withdrawal.

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“…Dynorphin is an endogenous opioid peptide generated from the precursor preprodynorphin, and it functions as a moderately selective agonist for the ksubtype of opioid receptors (Chavkin et al, 1982). Ventral tegmental area DA neurons receive inputs from dynorphinergic neurons and express k-receptors, and activation of these k-receptors depresses neuronal activity and DA release (Knoll and Carlezon, 2010;Wee and Koob, 2010). For example, exogenous k-agonists such as salvinorin A and U69593 decrease both mesolimbic DA release and behaviors such as ICSS that depend on mesolimbic DA release (Carlezon et al, 2006;Di Chiara and Imperato, 1988b;Negus et al, 2012;Todtenkopf et al, 2004;Zhang et al, 2005).…”

Section: Introductionmentioning

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 role of the dynorphin–κ opioid system in the reinforcing effects of drugs of abuse

Cited by 359 publications

References 159 publications

β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia

β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia

In Vivo Ethanol Experience Increases D2 Autoinhibition in the Ventral Tegmental Area

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

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