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: κ-opioid receptor

The molecular mechanisms mediating stress-induced dysphoria in humans and conditioned place aversion rodents are unknown. Here, we show that repeated swim stress caused activation of both κ-opioid receptor (KOR) p38 mitogen-activated protein kinase (MAPK) coexpressed GABAergic neurons the nucleus accumbens, cortex, hippocampus. Sites were visualized using phosphoselective antibodies against activated κ receptors (KOR-P) phospho-p38 MAPK. Surprisingly, increase P-p38-IR by swim-stress exposure was completely KOR dependent; did not KOR(−/−) knock-out mice subjected to same swim-paradigm or wild-type pretreated with antagonist norbinaltorphimine. To understand relationship between behavioral effects after activation, administered inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1 H -imidazole (i.c.v.)] found it selectively blocked agonist trans-3,4-dichloro- N -methyl- -[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide (U50488) KOR-dependent immobility while affecting analgesia nonselectively associative learning. We mechanism linking vivo consistent our previous vitro data suggesting β-arrestin recruitment is required; lacking G-protein-coupled 3 also failed p-p38-IR , immobility, develop U50488. Our results indicate MAPK signaling endogenous dynorphin-κ-opioid system likely constitutes a key component aversive properties stress.