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

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 -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 -receptor antagonists as promising therapeutics.

Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

“…The relationship between the CRF, adrenergic, and dynorphin systems in stress-induced reinstatement has not been resolved; however, we recently reported that CRF-induced place aversion was mediated by dynorphin-dependent KOR activation (Land et al 2008). Several additional lines of evidence support a possible dynorphin-CRF interaction in mediating stressinduced reinstatement.…”

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

“…Stress increases the levels of dynorphin (Nabeshima et al, 1992;Land et al, 2008;Bruchas et al, 2010), which is an endogenous KOR ligand (Chavkin et al, 1982). Both repeated forced swim stress and pharmacological activation of KORs with U50,488 increases ethanol consumption in mice (Sperling et al, 2010;Rose et al, 2015).…”

Corticotropin-Releasing Factor (CRF)-Induced Disruption of Attention in Rats Is Blocked by the κ-Opioid Receptor Antagonist JDTic

“…For example, the prototypical KOR antagonist nor-binaltorphimine (nor-BNI) blocks CRF-induced dysphoria in the place conditioning test (Land et al, 2008) and reductions in open arm time in the elevated plus maze (Bruchas et al, 2009). Our group has shown in preliminary tests that JDTic, another highly selective KOR antagonist that is structurally unrelated to nor-BNI (Carroll et al, 2004), also blocks CRF-induced elevations in acoustic startle behavior ( Van't Veer et al, 2011).…”

“…Our group has shown in preliminary tests that JDTic, another highly selective KOR antagonist that is structurally unrelated to nor-BNI (Carroll et al, 2004), also blocks CRF-induced elevations in acoustic startle behavior ( Van't Veer et al, 2011). The observations that CRF-induced phosphorylation of KORs is blocked by KOR antagonists (Land et al, 2008) and CRF-induced anxiety behavior is reduced in dynorphin knockout mice (Bruchas et al, 2009) provide molecular evidence for links between CRF and KOR systems. Interactions between these systems have been thoroughly characterized within the raphe nucleus (Bruchas et al, 2011) but may also occur in other brain regions (Pliakas et al, 2001;Newton et al, 2002;Shirayama et al, 2004;Muschamp et al, 2011b;Knoll et al, 2011).…”