期刊
JOURNAL OF NEUROSCIENCE
卷 28, 期 2, 页码 407-414出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4458-07.2008
关键词
dynorphin; aversion; stress-induced aversion; drug addiction; kappa-opioid receptor; corticotropin releasing factor
资金
- NIDA NIH HHS [DA16898, DA07278, F32 DA020430-02, DA20570, R01 DA016898-01, K05 DA020570-01, R01 DA016898, T32 DA007278-14, DA20430, R01 DA016898-04, F32 DA020430-01, T32 DA007278, R01 DA016898-03, K05 DA020570, F32 DA020430, R01 DA016898-02] Funding Source: Medline
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 kappa-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 kappa-receptor antagonists as promising therapeutics.
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