Source Paper
The Dysphoric Component of Stress Is Encoded by Activation of the Dynorphin κ-Opioid System
Benjamin B. Land, Michael R. Bruchas, Julia C. Lemos, Mei Xu, Erica J. Melief et al.
Journal of Neuroscience • 2008
View Abstract
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 κ-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 CRF 2 receptor antagonist antisauvigine-30, but not by the CRF 1 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 CRF 2 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 κ-receptor antagonists as promising therapeutics.
Inescapable Footshock
Objective: To produce aversive behaviors in mice through inescapable footshock stress and measure dysphoric responses
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Equipment1
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Protocol Steps
Inescapable footshock stress administration
Mice were exposed to inescapable footshock to induce stress and aversive behaviors
Note: This stress paradigm was presumed to evoke dysphoria in mice
View evidence from paper
“repeated forced swim and inescapable footshock both produced aversive behaviors that were blocked by a κ-opioid receptor antagonist”
Measurement of aversive behaviors
Aversive behaviors produced by inescapable footshock were measured and quantified
Note: Aversive behaviors were blocked by κ-opioid receptor antagonist and absent in dynorphin-deficient mice
View evidence from paper
“inescapable footshock both produced aversive behaviors that were blocked by a κ-opioid receptor (KOR) antagonist and absent in mice lacking dynorphin”