QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, January 9, 2008, 28(2):407-414; doi:10.1523/JNEUROSCI.4458-07.2008

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Land, B. B. Articles by Chavkin, C. Search for Related Content PubMed PubMed Citation Articles by Land, B. B. Articles by Chavkin, C.

 Previous Article  |  Next Article 

Behavioral/Systems/Cognitive
The Dysphoric Component of Stress Is Encoded by Activation of the Dynorphin -Opioid System

Benjamin B. Land,^1,2 * Michael R. Bruchas,^1 * Julia C. Lemos,² Mei Xu,¹ Erica J. Melief,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, University of Washington School of Medicine, Box 357280, Seattle, WA 98195-7280. Email: cchavkin{at}u.washington.edu

Stress is a complex human experience having both positive and negative motivational properties. When chronic and uncontrollable, the adverse effects of stress on human health are considerable and yet poorly understood. Here, we report that the dysphoric properties of chronic stress are encoded by the endogenous opioid peptide dynorphin acting on specific stress-related neuronal circuits. Using different forms of stress presumed to evoke dysphoria in mice, we found that repeated forced swim and inescapable footshock both produced aversive behaviors that were blocked by a -opioid receptor (KOR) antagonist and absent in mice lacking dynorphin. Injection of corticotropin-releasing factor (CRF) or urocortin III, key mediators of the stress response, produced place aversion that was also blocked by dynorphin gene deletion or KOR antagonism. CRF-induced place aversion was blocked by the CRF₂ receptor antagonist antisauvigine-30, but not by the CRF₁ receptor antagonist antalarmin. In contrast, place aversion induced by the KOR agonist U50,488 was not blocked by antisauvigine-30. These results suggest that the aversive effects of stress were mediated by CRF₂ receptor stimulation of dynorphin release and subsequent KOR activation. Using a phospho-selective antibody directed against the activated KOR to image sites of dynorphin action in the brain, we found that stress and CRF each caused dynorphin-dependent KOR activation in the basolateral amygdala, nucleus accumbens, dorsal raphe, and hippocampus. The convergence of stress-induced aversive inputs on the dynorphin system was unexpected, implicates dynorphin as a key mediator of dysphoria, and emphasizes -receptor antagonists as promising therapeutics.

Key words: dynorphin; aversion; stress-induced aversion; drug addiction; -opioid receptor; corticotropin releasing factor

---

Received Sept. 28, 2007; revised Nov. 13, 2007; accepted Nov. 19, 2007.

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

This article has been cited by other articles:

				B. M. Walker and G. F. Koob Regarding "Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake" FASEB J, July 1, 2008; 22(7): 2113 - 2113. [Full Text] [PDF]

				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]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help