Journal article
Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria
The Journal of neuroscience, Vol.27(43), pp.11614-11623
10/24/2007
DOI: 10.1523/JNEUROSCI.3769-07.2007
PMCID: PMC2481272
PMID: 17959804
Abstract
The molecular mechanisms mediating stress-induced dysphoria in humans and conditioned place aversion in rodents are unknown. Here, we show that repeated swim stress caused activation of both kappa-opioid receptor (KOR) and p38 mitogen-activated protein kinase (MAPK) coexpressed in GABAergic neurons in the nucleus accumbens, cortex, and hippocampus. Sites of activation were visualized using phosphoselective antibodies against activated kappa receptors (KOR-P) and against phospho-p38 MAPK. Surprisingly, the increase in P-p38-IR caused by swim-stress exposure was completely KOR dependent; P-p38-IR did not increase in KOR(-/-) knock-out mice subjected to the same swim-paradigm or in wild-type mice pretreated with the KOR antagonist norbinaltorphimine. To understand the relationship between p38 activation and the behavioral effects after KOR activation, we administered the p38 inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole (i.c.v.)] and found that it selectively blocked the conditioned place aversion caused by the kappa agonist trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide (U50488) and the KOR-dependent swim stress-induced immobility while not affecting kappa-opioid analgesia or nonselectively affecting associative learning. We found that the mechanism linking KOR and p38 activation in vivo was consistent with our previous in vitro data suggesting that beta-arrestin recruitment is required; mice lacking G-protein-coupled receptor kinase 3 also failed to increase p-p38-IR after KOR activation in vivo, failed to show swim stress-induced immobility, or develop conditioned place aversion to U50488. Our results indicate that activation of p38 MAPK signaling by the endogenous dynorphin-kappa-opioid system likely constitutes a key component of the molecular mechanisms mediating the aversive properties of stress.
Details
- Title: Subtitle
- Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria
- Creators
- Michael R Bruchas - Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USABenjamin B LandMegumi AitaMei XuSabiha K BarotShuang LiCharles Chavkin
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.27(43), pp.11614-11623
- DOI
- 10.1523/JNEUROSCI.3769-07.2007
- PMID
- 17959804
- PMCID
- PMC2481272
- NLM abbreviation
- J Neurosci
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Publisher
- United States
- Grant note
- T32 DA07278 / NIDA NIH HHS T32 DA007278-14 / NIDA NIH HHS F32 DA020430-02 / NIDA NIH HHS R01 DA016898-05 / NIDA NIH HHS R01 DA016898-01 / NIDA NIH HHS K05 DA020570-01 / NIDA NIH HHS K05 DA20570 / NIDA NIH HHS R01 DA016898-02 / NIDA NIH HHS F32 DA020430 / NIDA NIH HHS R01 DA016898 / NIDA NIH HHS R01 DA016898-04 / NIDA NIH HHS F32 DA020430-01 / NIDA NIH HHS T32 DA007278-13 / NIDA NIH HHS R01 DA16898 / NIDA NIH HHS K05 DA020570-02 / NIDA NIH HHS T32 DA007278 / NIDA NIH HHS R01 DA016898-03 / NIDA NIH HHS K05 DA020570 / NIDA NIH HHS
- Language
- English
- Date published
- 10/24/2007
- Academic Unit
- Periodontics
- Record Identifier
- 9984066098202771
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