http://usdbiology.com/cliff/Courses/Advanced%20Seminars%20in%20Neuroendocrinology/Anxiety%20and%20Decision%20Making/Koob%2008%20Neuron%20Brain%20Stress%20Systems%20in%20Addiction.pdf

A Role for Brain Stress Systems in Addiction

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.

https://www.jneurosci.org/content/jneuro/28/2/407.full.pdf

The Dysphoric Component of Stress Is Encoded by Activation of the Dynorphin κ-Opioid System

The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors

https://hal.archives-ouvertes.fr/hal-02437989/document

Opioid receptors: distinct roles in mood disorders

Dynorphin, stress, and depression

Stress and depression have been linked to relapse of cocaine abuse Antagonism of the kappa opioid receptor (KOR) has been reported to attenuate some effects of stressors, and antagonism of the KOR has been reported to have antidepressant-like properties Our objective was to determine whether the potent and selective KOR antagonist, (3R)-7-hydroxy-N-{(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), can reduce the ability of a stressor (intermittent footshock) to reinstate cocaine-seeking behavior and to have antidepressant-like effects in the forced swim test (FST) Male Long–Evans hooded rats were trained to lever-press, reinforced with 05 mg/kg iv infusion of cocaine, according to fixed ratio 1 reinforcement schedules during daily 2-h experimental sessions After performance had stabilized, lever pressing was extinguished for 12 consecutive sessions, and doses of 0 (vehicle), 3, 10, and 30 mg/kg JDTic were then administered ig to separate groups of 12 rats Twenty four hours later, the rats were given 15 min of intermittent footshock (087 mA, 05 s activation time, average interactivation interval of 40 s) or a 17-mg/kg ip administration of cocaine prime followed by a 2-h reinstatement test session JDTic was also evaluated for its ability to block diuresis induced by the KOR agonist, U50,488H (10 mg/kg, sc), during 5-h test sessions beginning 1 h after footshock reinstatement tests to verify its KOR antagonist activity In the FST, male Sprague–Dawley rats were treated with either nor-binaltorphimine (nor-BNI) or JDTic (both at 03, 1, 3, or 10 mg/kg, injected sc 23 h before), or desipramine (56, 10, or 17 mg/kg, injected ip 23, 5, and 1 h before) and placed in a cylinder of water, during which the predominance of immobility, swimming, and climbing were scored during 5-s intervals for 5 min The 10- and 30-mg/kg doses of JDTic significantly reduced footshock-induced reinstatement of responding previously reinforced by cocaine and significantly attenuated U50,488H-induced diuresis In contrast, JDTic did not affect cocaine-prime-induced reinstatement Both nor-BNI and JDTic decreased immobility and increased swimming time in the FST, similar to the antidepressant desipramine Depression and stress are two states during cocaine abstinence which users identify as precipitating relapse, and JDTic may have properties which attenuate both

Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats

James L. Howard

Papers

Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats