Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking

Abstract

Although stress has profound effects on motivated behavior, the underlying mechanisms responsible are incompletely understood. In this study we elucidate a functional pathway in mouse brain that encodes the aversive effects of stress and mediates stress-induced reinstatement of cocaine place preference (CPP). Activation of the dynorphin/kappa opioid receptor (KOR) system by either repeated stress or agonist produces conditioned place aversion (CPA). Because KOR inhibition of dopamine release in the mesolimbic pathway has been proposed to mediate the dysphoria underlying this response, we tested dopamine-deficient mice in this study and found that KOR agonist in these mice still produced CPA. However, inactivation of serotonergic KORs by injection of the KOR antagonist norBNI into the dorsal raphe nucleus (DRN), blocked aversive responses to the KOR agonist U50,488 and blocked stress-induced reinstatement of CPP. KOR knockout (KO) mice did not develop CPA to U50,488; however, lentiviral re-expression of KOR in the DRN of KOR KO mice restored place aversion. In contrast, lentiviral expression in DRN of a mutated form of KOR that fails to activate p38 MAPK required for KORdependent aversion, did not restore place aversion. DRN serotonergic neurons project broadly throughout the brain, but the inactivation of KOR in the nucleus accumbens (NAc) coupled with viral re-expression in the DRN of KOR KO mice demonstrated that aversion was encoded by a DRN to NAc projection. These results suggest that the adverse effects of stress may converge on the serotonergic system and offers an approach to controlling stress-induced dysphoria and relapse.depression ͉ drug addiction ͉ dynorphin ͉ serotonin S tress has profound effects on human health and can lead to mood disorders including clinical depression, anxiety, and can increase comorbid drug addiction risk (1-3). Corticotropin releasing factor (CRF) orchestrates the complex endocrine and neuronal responses to behavioral stress exposure (4), and recent studies have suggested that the dysphoric properties of stress are encoded by CRF-induced activation of the endogenous dynorphin opioid system (5). Systemic administration of kappa opioid receptor (KOR) antagonists block the aversive (5) and pro-addictive effects of stress (6-9), and dynorphin activation of KOR is thought to mediate opponent processes evoked by addictive drugs (10), yet the key sites of dynorphin/KOR action mediating these behavioral responses are not resolved.Mice subjected to behavioral stress show dynorphin release and robust KOR activation in both dopaminergic and serotonergic nuclei (5), implying that these neurotransmitters could be important for KOR-dependent stress-induced behavioral responses. Ventral tegmental area (VTA) dopaminergic projections to the nucleus accumbens (NAc) have been linked to addiction (11), making this an obvious target for the regulation of appetitive and aversive behaviors. However, prior studies have shown that mice lacking dopamine can still develop place preference for drugs of...

The role of the dynorphin/κ opioid receptor system in anxiety

“…The dorsal raphe nucleus (DRN), the primary source of serotonin that sends projections to multiple forebrain limbic regions, is critical for regulating affective states and stress [78] . Land et al (2009) demonstrated that the aversive properties of κ opioid receptor activation was encoded by DRN to NAc serotonergic projections because κ opioid receptor KO mice failed to develop κ opioid receptor agonist U50488-induced CPA; however, lentivirus expression of κ opioid receptors in the DRN restored the aversive response [79] , whereas lentivirus expression of mutated κ opioid receptors that were unable to activate p38 MAPK in the DRN did not restore the aversive response. In addition to mediating the dysphoric responses of stress, p38 MAPK activation within the DRN has also been found to contribute to depressive-like and drug-seeking behaviors [80] .…”

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

“…However, in vivo κOR activation is associated with side effects like anxiety, stress, diuresis, dysphoria/aversion, and psychomimetic effects (6)(7)(8). Also, activation of the κOR system has been implicated in relapse to drugs of abuse; this limits the use of κOR agonists in the treatment of drug addiction (13,14). Studies correlating the dysphoric effects of κOR agonists to the G-protein-independent activation of the p38 MAPK pathway (8,13,15) suggest that identification of κOR agonists biased to G-protein-mediated signaling could lead to the development of therapeutics with reduced side effects.…”

“…Also, activation of the κOR system has been implicated in relapse to drugs of abuse; this limits the use of κOR agonists in the treatment of drug addiction (13,14). Studies correlating the dysphoric effects of κOR agonists to the G-protein-independent activation of the p38 MAPK pathway (8,13,15) suggest that identification of κOR agonists biased to G-protein-mediated signaling could lead to the development of therapeutics with reduced side effects. This suggestion has spurred the search for novel κOR ligands or scaffolds that could provide novel treatment strategies for a variety of disorders where κOR involvement has been implicated (16,17).…”

6′-Guanidinonaltrindole (6′-GNTI) Is a G Protein-biased κ-Opioid Receptor Agonist That Inhibits Arrestin Recruitment

“…Interestingly, their dysphoric effects require activation of the p38 MAPK pathway mediated by arrestin recruitment to the activated KOR (4,10,11). KOR-induced p38 MAPK activation has been demonstrated in heterologous expression systems, striatal neurons and astrocytes, spinal cord astrocytes, and in vivo (12)(13)(14) and requires KOR phosphorylation by the G protein-coupled receptor kinase 3 (GRK3) and subsequent arrestin3 recruitment (12).…”