The Dysphoric Component of Stress Is Encoded by Activation of the Dynorphin κ-Opioid System
By Benjamin Land, M. Bruchas, Julia C. Lemos, Mei Xu, Erica J. Melief, C. Chavkin. Journal of Neuroscience, 2008
596 citations recorded by the source corpus.
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 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 κ-receptor antagonists as promising therapeutics.
Subfields: Behavioral Neuroscience, Cellular and Molecular Neuroscience, Social Psychology
View Paper: https://www.semanticscholar.org/paper/a6da9657d76de0d4b0214925c493bfa4250fd18f
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Citations in the corpus
- A role for brain stress systems in addiction. (2008, unknown): “Activation of dynorphin systems also may mediate a dysphoric component of stress (Land et al., 2008; McLaughlin et al., 2003).”
- Depression: An Evolutionarily Conserved Mechanism to Terminate Separation Distress? A Review of Aminergic, Peptidergic, and Neural Network Perspectives (2009, background): “As noted earlier, one recent important finding is that many CRF stress effects are secondarily mediated through changes in downstream dynorphin dynamics, which potentially promotes shutdown of the ventral tegmental area (VTA) (Land et al., 2008).”