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Review
. 2012 Oct;35(10):587-96.
doi: 10.1016/j.tins.2012.05.005. Epub 2012 Jun 16.

κ-opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction

Eduardo R Butelman  1 , Vadim Yuferov, Mary Jeanne Kreek
Affiliations
Review

κ-opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction

Eduardo R Butelman et al. Trends Neurosci. 2012 Oct.

Abstract

Addictions to cocaine or heroin/prescription opioids [short-acting μ-opioid receptor (MOPr) agonists] involve relapsing cycles, with experimentation/escalating use, withdrawal/abstinence, and relapse/re-escalation. κ-Opioid receptors (KOPr; encoded by OPRK1), and their endogenous agonists, the dynorphins (encoded by PDYN), have counter-modulatory effects on reward caused by cocaine or MOPr agonist exposure, and exhibit plasticity in addictive-like states. KOPr/dynorphin activation is implicated in depression/anxiety, often comorbid with addictions. In this opinion article we propose that particular stages of the addiction cycle are differentially affected by KOPr/dynorphin systems. Vulnerability and resilience can be due to pre-existing (e.g., genetic) factors, or epigenetic modifications of the OPRK1 or PDYN genes during the addiction cycle. Pharmacotherapeutic approaches limiting changes in KOPr/dynorphin tone, especially with KOPr partial agonists, may hold potential for the treatment of specific drug addictions and psychiatric comorbidity.

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Figures

Figure Legend 1
Figure Legend 1. Different stages of the addiction cycle and potential KOPr-directed pharmatherapeutic opportunities
(a) Operational stages of the addiction-cycle to cocaine, heroin or illicitly used prescription opioids. Individual trajectory (e.g., severity of escalation, withdrawal, or risk of relapse) is thought to depend on major interacting factors: extent of drug exposure, concomitant stresses, co-morbid psychiatric / psychological status and genetic predisposition (e.g., in OPRK1/PDYN or OPRM1 genes) [, , , , , , –100]. Each of these factors may be hypothesized to have particular impact at a specific operational stage. For example, a particular SNP may exacerbate either acquisition/escalation, severity of withdrawal-induced dysphoria, or probability of relapse. (b) Proposed pharmacotherapeutic approaches for addictions and neuropsychiatric co-morbidity (panel B), based on appropriate modulation of KOPr/dynorphin tone with selective antagonists or partial agonists. Selective KOPr antagonists (including recently reported compounds with durations of action that are within the range of most therapeutically used compounds [90]) may reduce relapse probability in the early stages of withdrawal/abstinence, by decreasing anhedonia, dysphoria, stress responsivity or comorbid psychiatric signs that may be secondary to upregulated KOPr/dynorphin tone [14, 15, 46, 50, 51, 90]. It is hypothesized that selective KOPr partial agonists (not currently available, due to lack of KOPr>MOPr selectivity in known ligands) [93, 95, 101] may be beneficial in promoting more prolonged abstinence, as well as decreasing the severity of relapse episodes. More specifically, a selective KOPr partial agonist can be hypothesized to provide a degree of homeostatic tone in the KOPr system, via blocking dynorphin-induced hyper-activation in the system (a factor in relapse; see panel (a)), as well as limiting excessive dopamine surges due to relapse-related exposure to cocaine or heroin/prescription opioids.
Figure Legend 2
Figure Legend 2
Gene structures and selected loci of genetic variability in human (a) PDYN, (b) OPRK1 and (c) OPRM1 genes in the context of addiction to drugs of abuse (eg. cocaine, heroin, methamphetamine and alcohol). Coding regions of exons are shown in green; 5′- and 3′- untranslated regions (UTR) are in black. The numbers refer to the polymorphisms given in Table 1. The location of the rs1997794 polymorphism (ie. #3) in the PDYN gene is shown in relation to the transcription initiation site; location of 17C>T (#2) and 118A>G (#3) in OPRM1 is shown in relation to ATG (a translation initiation site).
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