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

• DOI: 10.1523/jneurosci.3769-07.2007
• Publication Date: 2007-10-24T14:56:17Z
• Authors: Michael R. Bruchas; Benjamin B. Land; Megumi Aita; Mei Xu; Sabiha K. Barot; Shuang Li; Charles Chavkin
• Keywords: Mice, Knockout; 0301 basic medicine; Depression; Receptors, Opioid, kappa; p38 Mitogen-Activated Protein Kinases; Analgesics, Opioid; Enzyme Activation; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Animals; Enzyme Inhibitors; Stress, Psychological

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 activationin vivowas consistent with our previousin vitrodata suggesting that β-arrestin recruitment is required; mice lacking G-protein-coupled receptor kinase 3 also failed to increase p-p38-IR after KOR activationin 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.