Stress-Induced p38 Mitogen-Activated Protein Kinase Activation Mediates κ-Opioid-Dependent Dysphoria

By M. Bruchas, Benjamin Land, M. Aita, Mei Xu, Sabiha K. Barot, Shuang Li, C. Chavkin. Journal of Neuroscience, 2007

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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 κ-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 κ 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 κ 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 κ-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 β-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-κ-opioid system likely constitutes a key component of the molecular mechanisms mediating the aversive properties of stress.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/441e3f58e8fc98c75dc69baef291e3f39a198162

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Citations in the corpus

The Dysphoric Component of Stress Is Encoded by Activation of the Dynorphin κ-Opioid System (2008, methodology): “We found that treatments able to block stress-induced CPA did not also block the associative learning mechanisms responsible for mediating cocaine-CPP or the associative learning mediating taste aversion (Bruchas et al., 2007).”