Advertisement

Psychotomimetic Effects of Kappa Opioid Receptor Agonists

  • Kate L. White
    Affiliations
    Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
    Search for articles by this author
  • Bryan L. Roth
    Correspondence
    Address correspondence to Bryan L. Roth, M.D., Ph.D., CB #7365, University of North Carolina–Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599-7365
    Affiliations
    Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina

    Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, North Carolina

    Program in Neuroscience, University of North Carolina School of Medicine, Chapel Hill, North Carolina

    Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina

    Neurodevelopmental Disorders Research Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina

    Division of Chemical Biology and Medicinal Chemistry, University of North Carolina School of Medicine, Chapel Hill, North Carolina

    National Institute of Mental Health Psychoactive Drug Screening Program, Chapel Hill, North Carolina
    Search for articles by this author
      The κ opioid receptor (KOR)-dynorphin system has been implicated in the pathogenesis and pathophysiology of affective disorders, drug addiction, and psychotic disorders (
      • Sheffler D.
      • Roth B.L.
      Salvinorin A: the “magic mint” hallucinogen finds a molecular target in the kappa opioid receptor.
      ). Within the brain, KOR expression is highest in regions implicated in the modulation of reward, mood, cognition, and perception (ventral tegmental area, nucleus accumbens, prefrontal cortex, hippocampus, striatum, amygdala, and hypothalamus). Accordingly, drugs directed at KOR as either antagonists or partial agonists have potential utility for a number of indications, especially as antidepressants and anxiolytics. Additionally, KOR agonists are gaining attention as potential antiaddiction medications and analgesics without a high abuse potential. However, the adverse effects produced by KOR agonists including aversion, sedation, dysphoria, and hallucinations have limited their clinical use. Understanding how KOR signaling discriminates between analgesia and the unwanted side effects may lead to the design of more successful therapies. Furthermore, understanding the molecular events involved in KOR-mediated hallucinations will enhance our understanding of cognition and perception.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic and Personal

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Sheffler D.
        • Roth B.L.
        Salvinorin A: the “magic mint” hallucinogen finds a molecular target in the kappa opioid receptor.
        Trends Pharmacol Sci. 2003; 3: 107-109
        • Roth B.L.
        • Baner K.
        • Westkaemper R.
        • Siebert D.
        • Rice K.C.
        • Steinberg S.
        • et al.
        Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist.
        Proc Natl Acad Sci USA. 2002; 18: 11934-11939
        • Gonzalez-Maeso J.
        • Weisstaub N.V.
        • Zhou M.
        • Chan P.
        • Ivic L.
        • Ang R.
        • et al.
        Hallucinogens recruit specific cortical 5-HT2a receptor-mediated signaling pathways to affect behavior.
        Neuron. 2007; 53: 439-452
        • Pfeiffer A.
        • Brantl V.
        • Herz A.
        • Emrich H.
        Psychotomimesis mediated by kappa opiate receptors.
        Science. 1986; 233: 774-776
        • Ranganathan M.
        • Schnakenberg A.
        • Skosnik P.D.
        • Cohen B.M.
        • Pittman B.
        • Sewell R.A.
        • D'Souza D.C.
        Dose-related behavioral, subjective, endocrine, and psychophysiological effects of the κ opioid agonist Salvinorin A in humans.
        Biol Psychiatry. 2012; 72: 871-879
        • Rasakham K.
        • Liu-Chen L.
        Sex differences in kappa opioid pharmacology.
        Life Sci. 2011; 88: 2-16
        • Carlezon Jr, W.A.
        • Beguin C.
        • Dinieri J.A.
        • Baumann M.H.
        • Richards M.R.
        • Todtenkopf M.S.
        • et al.
        Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats.
        J Pharmacol Exp Ther. 2006; 1: 440-447
        • Glick S.
        • Maisonneuve I.
        • Raucci J.
        • Archer S.
        Kappa opioid inhibition of morphine and cocaine self-administration in rats.
        Brain Res. 1995; 681: 147-152
        • Allen J.A.
        • Yost J.M.
        • Setola V.
        • Chen X.
        • Sassano M.F.
        • Chen M.
        • et al.
        Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy.
        PNAS. 2011; 108: 18488-18493
        • Bruchas M.R.
        • Land B.B.
        • Aita M.
        • Xu M.
        • Barot S.K.
        • Li S.
        • Chavkin C.
        Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria.
        J Neurosci. 2007; 43: 11614-11623

      Linked Article