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The Journal of Neuroscience, October 24, 2007, 27(43):11614-11623; doi:10.1523/JNEUROSCI.3769-07.2007

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Behavioral/Systems/Cognitive
Stress-Induced p38 Mitogen-Activated Protein Kinase Activation Mediates -Opioid-Dependent Dysphoria

Michael R. Bruchas,¹ Benjamin B. Land,² Megumi Aita,¹ Mei Xu,¹ Sabiha K. Barot,² Shuang Li,¹ and Charles Chavkin^1,2

¹Department of Pharmacology and ²Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, Washington 98195-7280

Correspondence should be addressed to Dr. Charles Chavkin, Department of Pharmacology, Box 357280, University of Washington School of Medicine, Seattle, WA 98195-7280. Email: cchavkin{at}u.washington.edu

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 -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 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 agonist trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide (U50488 [GenBank] ) and the KOR-dependent swim stress-induced immobility while not affecting -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 ß-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--opioid system likely constitutes a key component of the molecular mechanisms mediating the aversive properties of stress.

Key words: dynorphin; G-protein-coupled receptor kinase; ß-arrestin; aversion; stress-induced immobility; drug addiction; p38 MAPK; -opioid receptor

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Received Aug. 17, 2007; revised Sept. 10, 2007; accepted Sept. 10, 2007.

Correspondence should be addressed to Dr. Charles Chavkin, Department of Pharmacology, Box 357280, University of Washington School of Medicine, Seattle, WA 98195-7280. Email: cchavkin{at}u.washington.edu

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				G. V. Carr and S. D. Mague p38: The Link between the {kappa}-Opioid Receptor and Dysphoria J. Neurosci., March 5, 2008; 28(10): 2299 - 2300. [Full Text] [PDF]

				B. B. Land, M. R. Bruchas, J. C. Lemos, M. Xu, E. J. Melief, and C. Chavkin The Dysphoric Component of Stress Is Encoded by Activation of the Dynorphin {kappa}-Opioid System J. Neurosci., January 9, 2008; 28(2): 407 - 414. [Abstract] [Full Text] [PDF]

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