Trends in Neurosciences
Opinionκ-opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction
Introduction
The KOPr system and its endogenous agonist ligands, the dynorphins, are widely distributed in the central and peripheral nervous systems 1, 2, 3, 4, 5. Dynorphins are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing, multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neoendorphins 6, 7.
Behavioral, perceptual, reward- and mood processes, and neuroendocrine functions [e.g., in the hypothalamic–pituitary–adrenal (HPA) axis], are all modulated by the KOPr/dynorphin system. This system also interacts prominently with dopaminergic circuits, and some of the aforementioned effects of KOPr activation (e.g., on mood and reward) may be secondary to this dopaminergic modulation. Acute agonist-induced activation of the KOPr system can result in aversion/dysphoria/sedation (possibly related to anhedonia and decreased arousal) and also psychotomimesis in humans [8]. Potentially related to these psychotomimetic effects, the widely available hallucinogen salvinorin A (from the plant Salvia divinorum) is a high-efficacy selective KOPr agonist [9].
Administration of high-efficacy KOPr agonists causes depressant-like effects and anhedonia in rodents [10] and causes conditioned place aversion 11, 12. Upregulation in dynorphin mRNA levels occurs after exposure to stress or to drugs of abuse (e.g., cocaine or short-acting MOPr agonists, discussed below). Depressant-like or anhedonic effects observed after stress exposure or during cocaine withdrawal can be blocked by KOPr antagonists 13, 14, 15. These findings have led to the postulate that increased endogenous dynorphin-induced activation of KOPr (KOPr ‘tone’) can result in the above neuropsychiatric adverse events. Notably, there is considerable comorbidity of such psychiatric disorders in specific addictive disease patients 16, 17, 18.
The KOPr/dynorphin system is also upregulated by exposure to drugs of abuse such as stimulants (e.g., cocaine) and MOPr agonists 19, 20, 21, 22, 23. At a methodological level, it should be noted that plasticity in the KOPr target can be detected both at the mRNA level and the protein level (e.g., by autoradiography). By contrast, most data for plasticity in the dynorphin target are at the mRNA level because it is more demanding to obtain quantitative data on dynorphin peptides (e.g., due to antibody immunoreactivity and specificity problems). Overall, it may be postulated that KOPr/dynorphin upregulation plays specific roles depending on the stage within an addiction cycle (which operationally can include: initiation/escalation of exposure, withdrawal/abstinence and relapse/re-escalation; discussed further below). Other major systems (e.g., the glutamatergic system as well as neuropeptide modulators such as corticotropin-releasing factor (CRF) and vasopressin) are undoubtedly involved, but the scope of this article will be limited to the KOPr/dynorphin system.
The focus of this Opinion article is primarily on addictions to cocaine and short-acting MOPr agonists, and not directly on other substances such as nicotine, cannabinoids, or alcohol. Several valuable recent reviews have focused on the role of the KOPr/dynorphin systems in the neurobiology of addiction and comorbid neuropsychiatric states 24, 25, 26. The translational focus of this article is on how specific pharmacotherapeutic approaches focusing on this system (e.g., selective KOPr antagonists or partial agonists) may hold potential at different stages of the operationally defined addiction cycle. We further propose that specific human genetic variants in this system may affect vulnerability and resilience at particular stages of the addiction cycle to specific types of drugs, such as cocaine and other stimulants, or heroin or abused prescription opioids, and may thus further inform clinical treatment efforts.
Section snippets
Addiction states and their cyclical relapsing nature: a framework for the impact of the KOPr/dynorphin system
The trajectory of addiction has operational stages including early experimentation, escalating self-exposure, followed by withdrawal/abstinence periods of varying duration and, in vulnerable individuals, relapse/re-escalation of variable severity (Figure 1a) 27, 28, 29, 30, 31, 32. Some behavioral and neurobiological manifestations of these stages are specific to each drug of abuse. For example, neurobiological aspects of withdrawal can differ between stimulants, such as cocaine, and
Neurobiology of the KOPr/dynorphin system: impact upon the addiction cycle
KOPr and dynorphin peptides are localized in areas of the dopaminergic nigrostriatal and mesolimbic–mesocortical systems 2, 3. They play an important role in the modulation of reward, be it to natural reinforcers (e.g., food, appetitive stimuli) or to drugs of abuse (e.g., cocaine, a monoamine reuptake inhibitor, or MOPr agonists such as heroin), presumably through modulation of basal and reward/drug-induced changes in dopaminergic tone. In contrast to most drugs of abuse (e.g., stimulants,
Adaptations in the KOPr/dynorphin system after exposure to drugs of abuse
Expression of the PDYN gene is increased on an acute and recurrent basis by drugs of abuse such as cocaine 19, 20. Interestingly, this effect becomes more pronounced after chronic high-dose cocaine exposure, in dorsal striatal areas thought to be involved in compulsive/habit-like behaviors, one of the hallmarks of addictive states 19, 20, 53, 54. KOPr antagonists can block stress-induced reinstatement of cocaine self-administration or conditioned place preference (CPP), which are models for
Genetics of PDYN and vulnerability in the addiction cycle
Genetic polymorphisms in the PDYN gene [e.g., individual single nucleotide polymorphisms (SNPs), haplotypes, repeats, or insertion/deletions (indels)], may affect the efficiency of transcription or responsiveness to environmental or internal stimuli. This would in turn result in downstream neurobiological and behavioral adaptations (e.g., proximally through dynorphin agonist actions on KOPr). Therefore, genetic variation at PDYN, or epigenetic changes, could underlie susceptibility and
Pharmacotherapeutic implications: targeting neurobiological adaptations in the KOPr/dynorphin system at different stages of the addiction cycle
As detailed above, polymorphisms in genes of the opioid receptor system, or of genes encoding cognate endogenous neuropeptides, are postulated to be associated with vulnerability during specific stages of the addiction cycle. In some cases, information on such stage-specific roles is available. For example, polymorphisms in OPRM1 are associated with particular aspects of addiction susceptibility or treatment success [81]. It is also known that sufficient drug exposure (e.g., to cocaine) –
Concluding remarks
The KOPr/dynorphin system has emerged as a powerful regulator of the neurobehavioral consequences of acute and prolonged exposure to cocaine, heroin, or illicitly used prescription opioids. This system may also contribute to comorbid anxiety and depression, which may exacerbate particular stages in the addiction cycle. Genetic polymorphisms in PDYN and OPRK1 may be associated with vulnerability at different stages by conferring relative risk or protection in (i) initial escalation, (ii)
Acknowledgments
The authors gratefully acknowledge funding from the National Institutes of Health, National Institute on Drug Abuse (grant P60 DA05130), National Institute of Mental Health grant (MH70880), and National Center for Research Resources (Center for Clinical and Translational Science; grant UL1RR024143).
References (107)
Kappa 1 receptor mRNA distribution in the rat CNS: comparison to kappa receptor binding and prodynorphin mRNA
Mol. Cell. Neurosci.
(1994)The cloned mu, delta and kappa receptors and their endogenous ligands: evidence for two opioid peptide recognition cores
Brain Res.
(1995)Central kappa-opioid receptor-mediated antidepressant-like effects of nor-Binaltorphimine: behavioral and BDNF mRNA expression studies
Eur. J. Pharmacol.
(2007)Blockade of kappa opioid receptors attenuates the development of depressive-like behaviors induced by cocaine withdrawal in rats
Neuropharmacology
(2012)‘Binge’ cocaine administration induces a sustained increase of prodynorphin mRNA in rat caudate-putamen
Brain Res. Mol. Brain Res.
(1993)Acute intermittent morphine increases preprodynorphin and kappa opioid receptor mRNA levels in the rat brain
Brain Res. Mol. Brain Res.
(1999)The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors
Brain Res.
(2010)Neurobiology of the incubation of drug craving
Trends Neurosci.
(2011)1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial
Lancet
(2003)The association between outpatient buprenorphine detoxification duration and clinical treatment outcomes: a review
Drug Alcohol Depend.
(2011)