The Kappa Opioid Receptor: From Addiction to Depression, and Back

Abstract

Comorbidity is a major issue in psychiatry that notably associates with more severe symptoms, longer illness duration, and higher service utilization. Therefore, identifying key clusters of comorbidity and exploring the underlying pathophysiological mechanisms represent important steps toward improving mental health care. In the present review, we focus on the frequent association between addiction and depression. In particular, we summarize the large body of evidence from preclinical models indicating that the kappa opioid receptor (KOR), a member of the opioid neuromodulatory system, represents a central player in the regulation of both reward and mood processes. Current data suggest that the KOR modulates overlapping neuronal networks linking brainstem monoaminergic nuclei with forebrain limbic structures. Rewarding properties of both drugs of abuse and natural stimuli, as well as the neurobiological effects of stressful experiences, strongly interact at the level of KOR signaling. In addiction models, activity of the KOR is potentiated by stressors and critically controls drug-seeking and relapse. In depression paradigms, KOR signaling is responsive to a variety of stressors, and mediates despair-like responses. Altogether, the KOR represents a prototypical substrate of comorbidity, whereby life experiences converge upon common brain mechanisms to trigger behavioral dysregulation and increased risk for distinct but interacting psychopathologies.

Mechanisms Underlying Motivational Deficits in Psychopathology: Similarities and Differences in Depression and Schizophrenia

“…As described above, the animal literature suggests that hedonic responsivity is associated with opioid and GABA-ergic function in the striatum, and this pattern is consistent with the hypothesis that altered opioid function may contribute to hedonic impairment in depression. This hypothesis is also consistent with a growing literature on opioid mechanisms in depression (Lalanne et al 2014;Murphy 2015) and an emerging interest in modulation of the kappa opioid system as a treatment for depression (Connolly and Thase 2012), with a specific focus on anhedonia. At the same time, the results in depression could also suggest a role for altered DA function in the striatum.…”

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

“…The dysphoric properties of chronic stress are encoded by dynorphin acting on KOP-r in specific stress-related brain regions, as the dynorphin-dependent KOP-r activation by stress is found in these brain regions (including the basolateral amygdala, NAc, dorsal raphe, and hippocampus). Together, dynorphin/KOP-r system is a key mediator of stress induced aversion, dysphoria, and anxiety-and depression-like behaviors [Butelman et al, 2012;Lalanne et al, 2014]. Like stressors, KOP-r agonists stimulate HPA activity in rats, and selective KOP-r antagonist nor-BNI blocks the stimulatory effects of the KOP-r agonists on the HPA axis [e.g., Laorden and Milanes, 2000;Pascoe et al, 2008].…”

Behavioral Characterization of κ Opioid Receptor Agonist Spiradoline and Cannabinoid Receptor Agonist CP55940 Mixtures in Rats

“…There is a need for more effective treatments that have fewer of the deleterious effects that currently limit the clinical use of opioids. Unlike m opioid receptor agonists, synthetic k opioid receptor agonists are not likely to be abused because they are devoid of positive reinforcing effects Chavkin, 2011;Tejeda et al, 2013;Lalanne et al, 2014). The antinociceptive effects of k opioid receptor agonists are comparable to those of m opioid receptor agonists in various animal models of pain (Desmeules et al, 1993;Binder et al, 2001;Smith et al, 2008;Kivell and Prisinzano, 2010;Gerak and France, 2016); however, doses producing antinociception also produce conditioned place aversion and diuresis (Leander, 1983;Shippenberg and Herz, 1987;Zhang et al, 2005).…”