κ-opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction.
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.
Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Eduardo R
ER
Butelman
Vadim
V
Yuferov
Mary Jeanne
MJ
Kreek
D000220:Adaptation, Biological / Q000235:genetics / Q000502:physiology; D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D055808:Drug Discovery / Q000379:methods; D004399:Dynorphins / Q000502:physiology*; D004745:Enkephalins / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D013287:Illicit Drugs / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011498:Protein Precursors / Q000235:genetics; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D012008:Recurrence
D004745:Enkephalins; D013287:Illicit Drugs; D009292:Narcotic Antagonists; D011498:Protein Precursors; D017473:Receptors, Opioid, kappa; D004399:Dynorphins; C033660:preproenkephalin