Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials

Depress Anxiety. 2016 Oct;33(10):895-906. doi: 10.1002/da.22500.

Abstract

Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry. This research established that exposure to drugs of abuse or stress increases the activity of the transcription factor CREB (cAMP response element binding protein) in the NAc, which leads to elevated expression of the opioid peptide dynorphin that in turn causes core signs of depressive- and anxiety-related disorders. Disruption of KORs-the endogenous receptors for dynorphin-produces antidepressant- and anxiolytic-like actions in screening procedures that identify standard drugs of these classes, and reduces stress effects in tests used to study addiction and stress-related disorders. Although interest in this target is high, prototypical KOR antagonists have extraordinarily persistent pharmacodynamic effects that complicate clinical trials. The development of shorter acting KOR antagonists together with more rapid designs for clinical trials may soon provide insight on whether these drugs are efficacious as would be predicted by preclinical work. If successful, KOR antagonists would represent a unique example in psychiatry where the therapeutic mechanism of a drug class is understood before it is shown to be efficacious in humans.

Keywords: anxiety; anxiety disorders; mood disorders; pharmacotherapy; substance use disorders; treatment.

Publication types

  • Review

MeSH terms

  • Animals
  • Anti-Anxiety Agents / therapeutic use*
  • Antidepressive Agents / therapeutic use*
  • Anxiety Disorders / drug therapy*
  • Anxiety Disorders / physiopathology
  • Brain / drug effects
  • Brain / physiopathology
  • CREB-Binding Protein / genetics
  • Disease Models, Animal
  • Dynorphins / physiology*
  • Dynorphins / therapeutic use*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Humans
  • Narcotic Antagonists / therapeutic use*
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / physiopathology
  • Receptors, Opioid, kappa / antagonists & inhibitors*
  • Receptors, Opioid, kappa / physiology
  • Reward
  • Stress, Psychological / complications
  • Stress, Psychological / physiopathology
  • Substance-Related Disorders / complications
  • Substance-Related Disorders / physiopathology
  • Translational Medical Research

Substances

  • Anti-Anxiety Agents
  • Antidepressive Agents
  • Narcotic Antagonists
  • Receptors, Opioid, kappa
  • Dynorphins
  • CREB-Binding Protein
  • CREBBP protein, human