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The Role of Dynorphin and the Kappa Opioid Receptor in the Symptomatology of Schizophrenia: A Review of the Evidence

Open AccessPublished:May 26, 2019DOI:https://doi.org/10.1016/j.biopsych.2019.05.012

      Abstract

      Schizophrenia is a debilitating mental illness that affects approximately 1% of the world’s population. Despite much research in its neurobiology to aid in developing new treatments, little progress has been made. One system that has not received adequate attention is the kappa opioid system and its potential role in the emergence of symptoms, as well as its therapeutic potential. Here we present an overview of the kappa system and review various lines of evidence derived from clinical studies for dynorphin and kappa opioid receptor involvement in the pathology of both the positive and negative symptoms of schizophrenia. This overview includes evidence for the psychotomimetic effects of kappa opioid receptor agonists in healthy volunteers and their reversal by the pan–opioid antagonists naloxone and naltrexone and evidence for a therapeutic benefit in schizophrenia for 4 pan–opioid antagonists. We describe the interactions between kappa opioid receptors and the dopaminergic pathways that are disrupted in schizophrenia and the histologic evidence suggesting abnormal kappa opioid receptor signaling in schizophrenia. We conclude by discussing future directions.

      Keywords

      Schizophrenia is a debilitating mental illness that affects approximately 1% of the world’s population (
      • Karam C.S.
      • Ballon J.S.
      • Bivens N.M.
      • Freyberg Z.
      • Girgis R.R.
      • Lizardi-Ortiz J.E.
      • et al.
      Signaling pathways in schizophrenia: emerging targets and therapeutic strategies.
      ). It is characterized by a combination of positive symptoms (hallucinations, delusions, and disorganization), negative symptoms (flattened affect and social withdrawal), and cognitive symptoms (deficits in working memory, attention, and executive function) (
      • Goldman-Rakic P.S.
      Working memory dysfunction in schizophrenia.
      ,
      • Green M.F.
      What are the functional consequences of neurocognitive deficits in schizophrenia?.
      ,
      • Keefe R.S.
      • Eesley C.E.
      • Poe M.P.
      Defining a cognitive function decrement in schizophrenia.
      ).
      Kappa opioid receptors (KORs) play a critical role in modulating dopamine, serotonin, and glutamate release in the central nervous system. Dynorphin is a peptide neurotransmitter processed from its precursor prodynorphin and is the endogenous ligand of the KOR (
      • Chavkin C.
      • James I.F.
      • Goldstein A.
      Dynorphin is a specific endogenous ligand of the kappa opioid receptor.
      ). Dysregulation of the dynorphin/KOR system has been implicated in several psychiatric diseases, including schizophrenia, depression, bipolar disorder, and drug addiction (
      • Karam C.S.
      • Ballon J.S.
      • Bivens N.M.
      • Freyberg Z.
      • Girgis R.R.
      • Lizardi-Ortiz J.E.
      • et al.
      Signaling pathways in schizophrenia: emerging targets and therapeutic strategies.
      ,
      • Schwarzer C.
      30 years of dynorphins—New insights on their functions in neuropsychiatric diseases.
      ,
      • Darcq E.
      • Kieffer B.L.
      Opioid receptors: Drivers to addiction?.
      ). At least 2 compounds that function as KOR antagonists have entered clinical trials for mood disorders and cocaine addiction (
      • Ragguett R.-M.
      • Rong C.
      • Rosenblat J.D.
      • Ho R.C.
      • McIntyre R.S.
      Pharmacodynamic and pharmacokinetic evaluation of buprenorphine + samidorphan for the treatment of major depressive disorder.
      ,
      • Li W.
      • Sun H.
      • Chen H.
      • Yang X.
      • Xiao L.
      • Liu R.
      • et al.
      Major depressive disorder and kappa opioid receptor antagonists.
      ,
      • Carlezon Jr., W.A.
      • Krystal A.D.
      Kappa-opioid antagonists for psychiatric disorders: From bench to clinical trials.
      ,
      • Reed B.
      • Butelman E.R.
      • Fry R.S.
      • Kimani R.
      • Kreek M.J.
      Repeated administration of opra kappa (LY2456302), a novel, short-acting, selective KOP-r antagonist, in persons with and without cocaine dependence.
      ). Presented here is a review of the evidence for possible dynorphin and/or KOR involvement in both the positive and the negative symptoms of schizophrenia.

      KOR Agonists Are Psychotomimetics, and Their Psychotomimetic Effects Can Be Blocked With Opioid Receptor Antagonists Naloxone and Naltrexone

      In contrast to mu opioid receptor and delta opioid receptor agonists, KOR agonists are potent psychotomimetics in healthy people (Table 1). In the 1970s, as the need for analgesics with low potential for abuse grew, drug development focused on compounds that were selective agonists for the KOR rather than the mu opioid receptor. Rodent models showed that KOR agonists could produce strong analgesic effects without the potential for addiction. However, the use of the KOR agonist cyclazocine to treat opioid dependence resulted in psychotomimetic side effects (
      • Resnick R.B.
      • Fink M.
      • Freedman A.M.
      Cyclazocine treatment of opiate dependence: A progress report.
      ,
      • Hanlon T.E.
      • McCabe O.L.
      • Savage C.
      • Kurland A.A.
      A controlled comparison of cyclazocine and naloxone treatment of the paroled narcotic addict.
      ). It was shown that cyclazocine and ketocyclazocine could induce paranoid delusions and hallucinations of monsters (
      • Kumor K.M.
      • Haertzen C.A.
      • Johnson R.E.
      • Kocher T.
      • Jasinski D.
      Human psychopharmacology of ketocyclazocine as compared with cyclazocine, morphine and placebo.
      ). Interestingly, cyclazocine is also a mu opioid receptor antagonist, and its psychotomimetic side effects were rapidly reversed by administration of the kappa, mu, and delta opioid receptor antagonist naloxone, indicating that although delta opioid receptors could not be fully excluded, these psychotomimetic side effects most likely occurred through the kappa, rather than the mu or delta, opioid receptor (
      • Watson S.J.
      • Berger P.A.
      • Akil H.
      • Mills M.J.
      • Barchas J.D.
      Effects of naloxone on schizophrenia: Reduction in hallucinations in a subpopulation of subjects.
      ,
      • Jasinski D.R.
      • Martin W.R.
      • Sapira J.D.
      Antagonism of the subjective, behavioral, pupillary, and respiratory depressant effects of cyclazocine by naloxone.
      ) (Table 2). Initial studies in the development of synthetic benzomorphan KOR agonist MR 2033/2034 as an analgesic resulted in the subjects experiencing psychotomimetic symptoms, including disturbances in the perception of space and time, visual hallucinations, racing thoughts, feelings of body distortion, and discomfort (
      • Pfeiffer A.
      • Brantl V.
      • Herz A.
      • Emrich H.M.
      Psychotomimesis mediated by k opiate receptors.
      ). Similar to the effects of cyclazocine, these effects could also be blocked with naloxone (Table 2). Later trials with the selective KOR agonists enadoline, niravoline, and bremazocine as analgesics, and spiradoline in Parkinson’s disease, were discontinued when it was found that they caused psychotomimesis in healthy volunteers (
      • Reece P.A.
      • Sedman A.J.
      • Rose S.
      • Wright D.S.
      • Dawkins R.
      • Rajagopalan R.
      Diuretic effects, pharmacokinetics, and safety of a new centrally acting kappa-opioid agonist (CI-977) in humans.
      ,
      • Giuffra M.
      • Mouradian M.
      • Davis T.
      • Ownby J.
      • Chase T.
      Dynorphin agonist therapy of Parkinson's disease.
      ,
      • Gadano A.
      • Moreau R.
      • Pessione F.
      • Trombino C.
      • Giuily N.
      • Sinnassamy P.
      • et al.
      Aquaretic effects of niravoline, a κ-opioid agonist, in patients with cirrhosis.
      ,
      • Walsh S.L.
      • Strain E.C.
      • Abreu M.E.
      • Bigelow G.E.
      Enadoline, a selective kappa opioid agonist: Comparison with butorphanol and hydromorphone in humans.
      ,
      • Wadenberg M.L.
      A review of the properties of spiradoline: A potent and selective k-opioid receptor agonist.
      ,
      • Dortch-Carnes J.
      • Potter D.E.
      Bremazocine: A κ-opioid agonist with potent analgesic and other pharmacologic properties.
      ).
      Table 1Kappa Opioid Receptor (KOR) Agonists Cause Psychotomimesis in Healthy Volunteers
      StudyDrugMechanismEffect in Healthy Volunteers
      Resnick et al., 1971
      • Resnick R.B.
      • Fink M.
      • Freedman A.M.
      Cyclazocine treatment of opiate dependence: A progress report.
      , Hanlon et al., 1975
      • Hanlon T.E.
      • McCabe O.L.
      • Savage C.
      • Kurland A.A.
      A controlled comparison of cyclazocine and naloxone treatment of the paroled narcotic addict.
      , Kumor et al., 1986
      • Kumor K.M.
      • Haertzen C.A.
      • Johnson R.E.
      • Kocher T.
      • Jasinski D.
      Human psychopharmacology of ketocyclazocine as compared with cyclazocine, morphine and placebo.
      Cyclazocine, ketocyclazocineKOR agonist and mu receptor antagonistPsychotomimesis
      Pfeiffer et al., 1986
      • Pfeiffer A.
      • Brantl V.
      • Herz A.
      • Emrich H.M.
      Psychotomimesis mediated by k opiate receptors.
      MR 2033/2034KOR agonistPsychotomimesis
      Giuffra et al., 1993
      • Giuffra M.
      • Mouradian M.
      • Davis T.
      • Ownby J.
      • Chase T.
      Dynorphin agonist therapy of Parkinson's disease.
      SpiradolineKOR agonistPsychotomimesis
      Reece et al., 1994
      • Reece P.A.
      • Sedman A.J.
      • Rose S.
      • Wright D.S.
      • Dawkins R.
      • Rajagopalan R.
      Diuretic effects, pharmacokinetics, and safety of a new centrally acting kappa-opioid agonist (CI-977) in humans.
      EnadolineKOR agonistPsychotomimesis
      Gadano et al., 2000
      • Gadano A.
      • Moreau R.
      • Pessione F.
      • Trombino C.
      • Giuily N.
      • Sinnassamy P.
      • et al.
      Aquaretic effects of niravoline, a κ-opioid agonist, in patients with cirrhosis.
      NiravolineKOR agonistPsychotomimesis
      Dortch-Carnes and Potter 2005
      • Dortch-Carnes J.
      • Potter D.E.
      Bremazocine: A κ-opioid agonist with potent analgesic and other pharmacologic properties.
      BremazocineKOR agonistPsychotomimesis
      MacLean et al., 2013
      • MacLean K.A.
      • Johnson M.W.
      • Reissig C.J.
      • Prisinzano T.E.
      • Griffiths R.R.
      Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects.
      , Maqueda et al., 2016
      • Maqueda A.E.
      • Valle M.
      • Addy P.H.
      • Antonijoan R.M.
      • Puntes M.
      • Coimbra J.
      • et al.
      Naltrexone but not ketanserin antagonizes the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans.
      Salvinorin AKOR agonistPsychotomimesis
      Table 2The Psychotomimetic Effects of Selective Kappa Opioid Receptor (KOR) Agonists Can Be Blocked by Pretreatment With Opioid Antagonists
      StudyKOR AgonistAntagonistEffect in Healthy Volunteers
      Pfeiffer et al., 1986
      • Pfeiffer A.
      • Brantl V.
      • Herz A.
      • Emrich H.M.
      Psychotomimesis mediated by k opiate receptors.
      MR 2033/2034NaloxoneReversal of kappa-induced psychotomimetic effects
      Kumor et al., 1986
      • Kumor K.M.
      • Haertzen C.A.
      • Johnson R.E.
      • Kocher T.
      • Jasinski D.
      Human psychopharmacology of ketocyclazocine as compared with cyclazocine, morphine and placebo.
      Cyclazocine, ketocyclazocineNaloxoneReversal of kappa-induced psychotomimetic effects
      Maqueda et al., 2016
      • Maqueda A.E.
      • Valle M.
      • Addy P.H.
      • Antonijoan R.M.
      • Puntes M.
      • Coimbra J.
      • et al.
      Naltrexone but not ketanserin antagonizes the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans.
      Salvinorin ANaltrexoneReversal of kappa-induced psychotomimetic effects
      More recently, salvinorin A, the active compound in the world’s most potent hallucinogenic plant Salvia divinorum, was found to be a selective KOR agonist with greater than 5000 times selectivity for kappa over mu and delta receptors (
      • Roth B.L.
      • Baner K.
      • Westkaemper R.
      • Siebert D.
      • Rice K.C.
      • Steinberg S.
      • et al.
      Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist.
      ). Numerous studies of salvinorin A in healthy volunteers have documented its psychotomimetic effects (
      • Addy P.H.
      Acute and post-acute behavioral and psychological effects of salvinorin A in humans.
      ,
      • MacLean K.A.
      • Johnson M.W.
      • Reissig C.J.
      • Prisinzano T.E.
      • Griffiths R.R.
      Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects.
      ,
      • Maqueda A.E.
      • Valle M.
      • Addy P.H.
      • Antonijoan R.M.
      • Puntes M.
      • Coimbra J.
      • et al.
      Naltrexone but not ketanserin antagonizes the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans.
      ). MacLean et al. (
      • MacLean K.A.
      • Johnson M.W.
      • Reissig C.J.
      • Prisinzano T.E.
      • Griffiths R.R.
      Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects.
      ) performed a double-blind placebo-controlled study examining dose-dependent responses of salvinorin A in 8 healthy adult volunteers. They found that all of the volunteers reported interacting and communicating with “entities or beings” and 5 volunteers experienced visual and auditory hallucinations (
      • MacLean K.A.
      • Johnson M.W.
      • Reissig C.J.
      • Prisinzano T.E.
      • Griffiths R.R.
      Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects.
      ). Finally, in a double-blind study of 24 healthy volunteers, Maqueda et al. (
      • Maqueda A.E.
      • Valle M.
      • Addy P.H.
      • Antonijoan R.M.
      • Puntes M.
      • Coimbra J.
      • et al.
      Naltrexone but not ketanserin antagonizes the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans.
      ) found that salvinorin A produced both visual and auditory changes that could be blocked by the kappa, mu, and delta receptor antagonist naltrexone (Table 2).

      KOR Antagonists Have Immediate Antipsychotic Effects in Patients With Schizophrenia

      There have been at least 32 trials investigating the therapeutic potential of 4 different pan–opioid receptor antagonists in patients with schizophrenia. We present a narrative review of 21 trials of naloxone, 8 trials of naltrexone, 1 trial of nalmefene, and 2 trials of buprenorphine. Naloxone, naltrexone, and nalmefene are all antagonists at the kappa, mu, and delta receptors, and buprenorphine is a dual KOR antagonist and mu receptor partial agonist (Table 3). While many of these studies have shown impressive and rapid efficacy in the treatment of both positive and negative symptoms, some of these studies have shown mixed results ranging from nonsignificant trends toward improvement to complete lack of efficacy. Here we postulate that the mixed results may have been due to differences in trial design, including the dose and method of administration of the antagonist and time point at which the patient was assessed for effects of the drug. We propose that the success of these trials depended on that ability of each of these drugs to antagonize the KOR at physiologically relevant concentrations. Additionally, inclusion of patients with different core symptoms may introduce more heterogeneity. As schizophrenia is a heterogeneous disorder, it is possible that dynorphin and KOR dysregulation might represent a subset of patients with schizophrenia and that KOR antagonists may be less effective in patients without KOR dysregulation.
      Table 3Receptor Binding Affinity of Naloxone, Naltrexone, Buprenorphine, and Nalmefene at Cloned Human Receptors
      Data from Toll et al. (143).
      DrugKappa, nmol/LMu, nmol/LDelta, nmol/L
      Naloxone2.51.467.5
      Naltrexone0.40.210.8
      Buprenorphine0.81.5 (partial agonist)4.5
      Nalmefene0.30.37.3
      a Data from Toll et al.
      • Toll L.
      • Berzetei-Gurske I.P.
      • Polgar W.E.
      • Brandt S.R.
      • Adapa I.D.
      • Rodriguez L.
      • et al.
      Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications.
      .

      Naloxone Trials

      Naloxone is an extremely short-acting pan–opioid antagonist with a half-life of only 1 hour. In total, nearly all of these studies were designed to test for immediate effects on the positive symptoms of schizophrenia. Here we group them into 3 categories by dose: 1) 0.4 to 1.6 mg, 2) 4 to 10 mg, and 3) 20 mg to 2 mg/kg. Some of these categories can be further subdivided by method of administration. While some patients responded to the low dose range of 0.4 to 1.6 mg naloxone, most successful naloxone studies used at least 4 mg of naloxone delivered intravenously.
      In the first group of very-low-dose naloxone, there were 7 trials and 2 case reports (
      • Orr M.
      • Oppenheimer C.
      Effects of naloxone on auditory hallucinations.
      ,
      • Jørgensen H.A.
      • Cappelen C.
      Naloxone-induced reduction of schizophrenic symptoms: A case report.
      ) in patients with schizophrenia without catatonia who were administered a dose of 0.4 to 1.6 mg of intravenous (IV) naloxone with improvement on the Brief Psychiatric Rating Scale (BPRS) as an end point. Two trials found significant improvement (
      • Gunne L.-M.
      • Lindström L.
      • Terenius L.
      Naloxone-induced reversal of schizophrenic hallucinations.
      ,
      • Davis G.C.
      • Bunney W.E.
      • DeFraites E.G.
      • Kleinman J.E.
      • van Kammen D.P.
      • Post R.M.
      • Wyatt R.J.
      Intravenous naloxone administration in schizophrenia and affective illness.
      ), while the others reported mixed results (
      • Volavka J.
      • Mallya A.
      • Baig S.
      • Perez-Cruet J.
      Naloxone in chronic schizophrenia.
      ,
      • Janowsky D.S.
      • Segal D.S.
      • Bloom F.
      • Abrams A.
      • Guillemin R.
      Lack of effect on naloxone on schizophrenic symptoms.
      ,
      • Kurland A.A.
      • McCabe O.L.
      • Hanlon T.E.
      • Sullivan D.
      The treatment of perceptual disturbances in schizophrenia with naloxone hydrochloride.
      ,
      • Lipinski J.
      • Meyer R.
      • Kornetsky C.
      • Cohen B.
      Naloxone in schizophrenia: Negative result.
      ,
      • Freeman C.
      • Fairburn C.
      Lack of effect of naloxone and schizophrenic auditory hallucinations.
      ).
      Successful follow-up studies of naloxone in patients with schizophrenia later recognized that a dose of 0.4 to 1.6 mg is too low to occupy the majority of opioid receptors in the brain or to produce an observable effect in most patients with schizophrenia (
      • Emrich H.
      • Cording C.
      • Piree S.
      • Kölling A.
      • Zerssen D.
      • Herz A.
      Indication of an antipsychotic action of the opiate antagonist naloxone.
      ). For reference, positron emission tomography imaging has recently shown that a 1-mg bolus of IV naloxone in an 80-kg person leads to a maximum of 50% opioid receptor occupancy (Table 4) (
      • Melichar J.K.
      • Nutt D.J.
      • Malizia A.L.
      Naloxone displacement at opioid receptor sites measured in vivo in the human brain.
      ). Each of the negative studies also had very small sample sizes ranging from 6 to 12 patients, and with the exception of the work of Volavka et al. (
      • Volavka J.
      • Mallya A.
      • Baig S.
      • Perez-Cruet J.
      Naloxone in chronic schizophrenia.
      ) evaluated the patients only 1 hour post injection, a time frame that was later recognized as generally too short to produce an observable effect in most patients with schizophrenia (
      • Mueser K.T.
      • Dysken M.W.
      Narcotic antagonists in schizophrenia: A methodological review.
      ).
      Table 4Bioavailability and PET–Measured and Estimated Receptor Occupancy of Different Doses of Naloxone, Naltrexone, Buprenorphine, and Nalmefene
      DrugDose, mgRouteBioavailability, %Opioid Receptor Occupancy via PET, %
      Naloxone1IV100∼50a
      Naloxone0.8SC/IM36bNot reported
      Naltrexone100Oral5–60c∼87d
      Buprenorphine0.2SL49–63eNot reported
      Nalmefene20Oral41f87–100g
      Data from aMelichar et al.
      • Melichar J.K.
      • Nutt D.J.
      • Malizia A.L.
      Naloxone displacement at opioid receptor sites measured in vivo in the human brain.
      , bDowling et al.
      • Dowling J.
      • Isbister G.K.
      • Kirkpatrick C.M.
      • Naidoo D.
      • Graudins A.
      Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers.
      , cGonzalez et al.
      • Gonzalez J.P.
      • Brogden R.N.
      Naltrexone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence.
      , dVijay et al.
      • Vijay A.
      • Morris E.
      • Goldberg A.
      • Petrulli J.
      • Liu H.
      • Huang Y.
      • Krishnan-Sarin S.
      Naltrexone occupancy at kappa opioid receptors investigated in alcoholics by PET occupancy at kappa opioid receptors investigated in alcoholics by PET.
      , eElkader et al.
      • Elkader A.
      • Sproule B.
      Buprenorphine: Clinical pharmacokinetics in the treatment of opioid dependence.
      , fKyhl et al.
      • Kyhl L.E.
      • Li S.
      • Faerch K.U.
      • Soegaard B.
      • Larsen F.
      • Areberg J.
      Population pharmacokinetics of nalmefene in healthy subjects and its relation to μ-opioid receptor occupancy.
      , and gIngman et al.
      • Ingman K.
      • Hagelberg N.
      • Aalto S.
      • Någren K.
      • Juhakoski A.
      • Karhuvaara S.
      • et al.
      Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing.
      .
      IM, intramuscular; IV, intravenous; PET, positron emission tomography; SC, subcutaneous; SL, sublingual.
      The second group of naloxone studies administered doses of 4 to 10 mg and also used BPRS as the end point. In this group, there are 5 studies that, in contrast to those that used lower doses, were generally much more rigorously designed, as reflected by longer duration and larger sample sizes. Of the 5 studies, 4 (
      • Watson S.J.
      • Berger P.A.
      • Akil H.
      • Mills M.J.
      • Barchas J.D.
      Effects of naloxone on schizophrenia: Reduction in hallucinations in a subpopulation of subjects.
      ,
      • Emrich H.
      • Cording C.
      • Piree S.
      • Kölling A.
      • Zerssen D.
      • Herz A.
      Indication of an antipsychotic action of the opiate antagonist naloxone.
      ,
      • Lehmann H.E.
      • Cooper T.H.
      • Nair N.P.V.
      • Kline N.S.
      Beta-endorphins and naloxone in psychiatric patients: Clinical and biological effects.
      ,
      • Berger P.
      • Watson S.
      • Akil H.
      • Barchas J.
      The effects of naloxone in chronic schizophrenia.
      ) found statistically significant improvement from IV administration of naloxone. The 1 study that did not find improvement used subcutaneous rather than IV injection for most of the doses (
      • Naber D.
      • Münch U.
      • Wissmann J.
      • Grosse R.
      • Ritt R.
      • Welter D.
      Naloxone treatment for five days ineffective in schizophrenia.
      ). Subcutaneous and intramuscular administration of naloxone are considered to have similar pharmacokinetics, with only 36% bioavailability compared with that of IV administration (Table 4) (
      • Dowling J.
      • Isbister G.K.
      • Kirkpatrick C.M.
      • Naidoo D.
      • Graudins A.
      Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers.
      ).
      The third group of naloxone studies consists of 7 studies that used doses above 10 mg, ranging from 20 mg to 2 mg/kg. Similar to results of studies in the second group, results of these studies showed that persons who received IV administration of naloxone tended to demonstrate significant improvement on BPRS (
      • Emrich H.
      • Höllt V.
      • Laspe H.
      • Fischler M.
      • Heinemann H.
      • Kissling W.
      • et al.
      Studies on a possible pathological significance of endorphins in psychiatric disorders.
      ,
      • Kleinman J.E.
      • Weinberger D.R.
      • Rogol A.
      • Shiling D.J.
      • Mendelson W.B.
      • Davis G.C.
      • et al.
      Naloxone in chronic schizophrenic patients: neuroendocrine and behavioral effects.
      ,
      • Cohen M.R.
      • Pickar D.
      • Cohen R.M.
      High-dose naloxone administration in chronic schizophrenia.
      ), while those who received subcutaneous or intramuscular administration showed mixed results (
      • Emrich H.
      • Bergmann M.
      • Kissling W.
      • Schmid W.
      • Zerssen D.
      • Costa A.H.E.
      • Trabucchi M.
      Neural Peptides and Neuronal Communication.
      ,
      • Sethi BB Prakash R.
      A study of naloxone with schizophrenic and manic patients.
      ,
      • Naber D.
      • Leibl K.
      Repeated high dosage naloxone treatment without therapeutic efficacy in schizophrenic patients.
      ,
      • Verhoeven W.M.
      • Van Praag H.M.
      • Van Ree J.M.
      Repeated naloxone administration in schizophrenia.
      ).
      In one of the largest double-blind placebo-controlled crossover studies of naloxone in schizophrenia, Pickar et al. (
      • Pickar D.
      • Vartanian F.
      • Bunney W.E.
      • Maier H.P.
      • Gastpar M.T.
      • Prakash R.
      • et al.
      Short-term naloxone administration in schizophrenic and manic patients: A World Health Organization collaborative study.
      ) recruited 32 patients with schizophrenia (19 medicated and 13 unmedicated) and 26 patients with mania from 6 international trial sites. Each patient received a single subcutaneous 0.3-mg/kg dose of either naloxone or saline followed by a washout. When combining both the medicated and unmedicated groups with schizophrenia, they found a significant improvement in only the BPRS Hallucinatory Behavior subscale. In the medication-treated patients, they also found a significant improvement in total BPRS as well as in the Paranoid-Suspicion and Anxiety-Depression subscales. The medicated group also showed a significant improvement in the self-rated Auditory Hallucination subscale. In contrast to the patients with schizophrenia, the patients with mania did not show any improvement in symptoms, leading the authors to conclude that while naloxone had efficacy in schizophrenia, it was without efficacy in mania.
      In the final study of naloxone in patients with schizophrenia, Pickar et al. (
      • Pickar D.
      • Bunney W.
      • Douillet P.
      • Sethi B.
      • Sharma M.
      • Vartanian M.
      • et al.
      Repeated naloxone administration in schizophrenia: a phase II World Health Organization study.
      ) conducted a World Health Organization phase 2 double-blind placebo-controlled crossover study in 43 patients with schizophrenia. They did not replicate their previous results because of a large placebo response.

      Naltrexone Trials

      In contrast to the naloxone trials, where patients were usually evaluated within hours after a single dose, the naltrexone trials administered daily dosages for weeks to months and could test efficacy on the negative symptoms. In addition, there were a number of trials testing the ability of naltrexone to help sustain abstinence in dual-diagnosed patients with schizophrenia and co-occurring alcohol abuse disorder, which we will not consider here. We will consider the naltrexone trials grouped into 2 daily dosage ranges: 1) 100 mg/day and 2) >100 mg/day. The results of these studies show that 100 mg of naltrexone was a generally successful oral dose for treating the positive and negative symptoms of schizophrenia. Positron emission tomography imaging has shown that this dosage produces an average of 87% KOR occupancy (Table 4) (
      • Vijay A.
      • Morris E.
      • Goldberg A.
      • Petrulli J.
      • Liu H.
      • Huang Y.
      • Krishnan-Sarin S.
      Naltrexone occupancy at kappa opioid receptors investigated in alcoholics by PET occupancy at kappa opioid receptors investigated in alcoholics by PET.
      ).
      There were 3 studies with 100 mg/day naltrexone as the dosage. Of these, 2 were conducted by Marchesi et al. (
      • Marchesi G.
      • Santone G.
      • Cotani P.
      • Giordano A.
      • Chelli F.
      Naltrexone in chronic negative schizophrenia.
      ,
      • Marchesi G.F.
      • Santone G.
      • Cotani P.
      • Giordano A.
      • Chelli F.
      The therapeutic role of naltrexone in negative symptom schizophrenia.
      ), and 100 mg/day naltrexone was administered for 2 weeks, with improvement in the Clinical Global Impression scale and BPRS over placebo as the end points. In the first study, in 12 patients, the drug group showed a statistically significant improvement in total BPRS and negative schizophrenia symptoms versus those at baseline, while the placebo group did not show a statistical improvement (
      • Marchesi G.
      • Santone G.
      • Cotani P.
      • Giordano A.
      • Chelli F.
      Naltrexone in chronic negative schizophrenia.
      ). In the second study, in 1995, Marchesi et al. found a statistically significant improvement in negative symptoms compared to those at baseline in 18 patients (
      • Marchesi G.F.
      • Santone G.
      • Cotani P.
      • Giordano A.
      • Chelli F.
      The therapeutic role of naltrexone in negative symptom schizophrenia.
      ).
      Finally, in the largest and most rigorous study of opioid receptor antagonists in patients with schizophrenia to date, Tatari et al. (
      • Tatari F.
      • Shakeri J.
      • Farnia V.
      • Hashemian A.
      • Rezaei M.
      • Abdoli N.
      Naltrexone augmentation of risperidone in treatment of schizophrenia symptoms: A randomized placebo-controlled study.
      ) randomized 60 patients who were all stabilized on risperidone to 100 mg/day naltrexone or placebo for 12 weeks. They found significant improvement of both positive and negative symptoms in the drug group versus that of the placebo group, as assessed by the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms.
      There were 5 studies of naltrexone with dosages greater than 100 mg/day with BPRS as the end point. These studies suffered from either very small sample sizes or very short durations, and most were without either placebo control or blinding, or both (
      • Mielke D.H.
      • Gallant D.M.
      An oral opiate antagonist in chronic schizophrenia: A pilot study.
      ,
      • Simpson G.
      • Branchey M.
      • Lee J.
      Trial of naltrexone in chronic-schizophrenia.
      ,
      • Ragheb M.
      • Berney S.
      • Ban T.
      Naltrexone in chronic schizophrenia.
      ,
      • Gitlin M.J.
      • Gerner R.H.
      • Rosenblatt M.
      Assessment of naltrexone in the treatment of schizophrenia.
      ). Sernyak et al. (
      • Sernyak M.J.
      • Glazer W.M.
      • Heninger G.R.
      • Charney D.S.
      • Woods S.W.
      • Petrakis I.L.
      • et al.
      Naltrexone augmentation of neuroleptics in schizophrenia.
      ) planned to test 200 mg/day naltrexone in 21 patients with schizophrenia stabilized on typical antipsychotics. This was initially designed as a double-blind placebo-controlled crossover trial, but halfway into the trial, the blind was broken and many of the patients were not crossed over to the comparator arm.

      Trials With Other Opioid Antagonists

      In addition to the previously discussed naloxone and naltrexone trials, there was one successful trial with nalmefene and two with buprenorphine.
      In a double-blind placebo-controlled trial, Schmauss et al. (
      • Schmauss C.
      • Yassouridis A.
      • Emrich H.M.
      Antipsychotic effect of buprenorphine in schizophrenia.
      ) administered 0.2 mg of sublingual buprenorphine, a mu opioid receptor partial agonist and KOR antagonist, to 10 medication-free patients with schizophrenia with active positive symptoms. Buprenorphine exhibited an immediate antipsychotic effect on the Inpatient Multidimensional Psychiatric Scale in 7 of the patients but was ineffective in 3 patients previously diagnosed with residual schizophrenia. In an open study, Groves and Nutt (
      • Groves S.
      • Nutt N.J.
      Buprenorphine and schizophrenia.
      ) administered a single dose of 0.2 mg of sublingual buprenorphine to 7 patients with schizophrenia who were on antipsychotic medications. They found an immediate reduction in BPRS scores, particularly in the auditory hallucinations and mood scales.
      In 1993, Rapaport et al. (
      • Rapaport M.H.
      • Wolkowitz O.
      • Kelsoe J.R.
      • Pato C.
      • Konicki P.E.
      • Pickar D.
      Beneficial effects of nalmefene augmentation in neuroleptic-stabilized schizophrenic patients.
      ) tested nalmefene in a double-blind placebo-controlled crossover trial in 10 patients with schizophrenia who were on antipsychotics for an average of 36.7 days. They found a significant improvement over baseline in the BPRS thinking disturbance subscale and nurse-rated Bunney-Hamburg psychosis scale, and a trend toward significance in the physician-rated Bunney-Hamburg psychosis scale.

      Conclusions

      In summary, pan–opioid antagonists may have a therapeutic effect on both the positive and negative symptoms of schizophrenia. When viewed in light of the psychotomimetic effects of selective KOR agonists, these trials support the hypothesis that the therapeutic effect of pan–opioid antagonists may be mediated through the KOR.

      KORs Modulate the Dopamine Pathways Disrupted in Schizophrenia

      While the role of dopamine in schizophrenia was first hypothesized in the 1960s, the theory that endogenous opioid peptides and their receptors may play a role in the symptoms of schizophrenia was developed more than 10 years later, in the 1970s. Upon the realization that the endogenous opioid system plays a major role in dopamine regulation, researchers hypothesized a potential link between the two theories. They postulated that the dopamine imbalance in schizophrenia may be a downstream consequence of a disrupted opioid system (
      • Volavka J.
      • Davis L.G.
      • Ehrlich Y.H.
      Endorphins, dopamine, and schizophrenia.
      ,
      • Schmauss C.
      • Emrich H.M.
      Dopamine and the action of opiates: A reevaluation of the dopamine hypothesis of schizophrenia with special consideration of the role of endogenous opioids in the pathogenesis of schizophrenia.
      ).
      Imaging studies in patients with schizophrenia using positron emission tomography and single-photon emission computed tomography have shown an excess of presynaptic striatal dopamine and a deficiency of cortical dopamine (
      • Weinstein J.J.
      • Chohan M.O.
      • Slifstein M.
      • Kegeles L.S.
      • Moore H.
      • Abi-Dargham A.
      Pathway-specific dopamine abnormalities in schizophrenia.
      ,
      • Slifstein M.
      • van de Giessen E.
      • Van Snellenberg J.
      • Thompson J.L.
      • Narendran R.
      • Gil R.
      • et al.
      Deficits in prefrontal cortical and extrastriatal dopamine release in schizophrenia: A positron emission tomographic functional magnetic resonance imaging study.
      ). The cortical dopamine deficiency observed in the mesocortical pathway has been hypothesized to play a role in the negative and cognitive symptoms of schizophrenia (
      • Weinberger D.R.
      • Berman K.F.
      Speculation on the meaning of cerebral metabolic hypofrontality in schizophrenia.
      ,
      • Weinberger D.R.
      • Berman K.F.
      • Illowsky B.P.
      Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia: III. A new cohort and evidence for a monoaminergic mechanism.
      ). The increased presynaptic release of dopamine observed in the striatum of patients with schizophrenia has long been thought to play a critical role in the positive symptoms of schizophrenia. While both the ventral and dorsal striatum have shown increased dopamine release, the magnitude of the increase is much greater in the nigrostriatal pathway to the dorsal striatum, and particularly in the rostral caudate (
      • Weinstein J.J.
      • Chohan M.O.
      • Slifstein M.
      • Kegeles L.S.
      • Moore H.
      • Abi-Dargham A.
      Pathway-specific dopamine abnormalities in schizophrenia.
      ).

      A Possible Role for KORs in the Positive Symptoms of Schizophrenia

      KORs are present on presynaptic axons of the mesolimbic and nigrostriatal dopamine pathways throughout the striatum (
      • Schwarzer C.
      30 years of dynorphins—New insights on their functions in neuropsychiatric diseases.
      ,
      • Steiner H.
      • Gerfen C.R.
      Dynorphin regulates D1 dopamine receptor-mediated responses in the striatum: Relative contributions of pre-and postsynaptic mechanisms in dorsal and ventral striatum demonstrated by altered immediate-early gene induction.
      ,
      • Svingos A.L.
      • Chavkin C.
      • Colago E.E.
      • Pickel V.M.
      Major coexpression of κ-opioid receptors and the dopamine transporter in nucleus accumbens axonal profiles.
      ,
      • Escobar A.P.
      • González M.P.
      • Meza R.C.
      • Noches V.
      • Henny P.
      • Gysling K.
      • et al.
      Mechanisms of kappa opioid receptor potentiation of dopamine D2 receptor function in quinpirole-induced locomotor sensitization in ratsKOR potentiation of D2R-induced behavior.
      ,
      • Bruijnzeel A.W.
      kappa-Opioid receptor signaling and brain reward function.
      ) (Figure 1A), where they negatively regulate dopamine release (
      • Di Chiara G.
      • Imperato A.
      Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats.
      ) and represent an important mechanism for maintaining dopamine homeostasis and synaptic plasticity (
      • Hawes S.L.
      • Salinas A.G.
      • Lovinger D.M.
      • Blackwell K.T.
      Long-term plasticity of corticostriatal synapses is modulated by pathway-specific co-release of opioids through κ-opioid receptors.
      ,
      • Tejeda H.A.
      • Wu J.
      • Kornspun A.R.
      • Pignatelli M.
      • Kashtelyan V.
      • Krashes M.J.
      • et al.
      Pathway-and cell-specific kappa-opioid receptor modulation of excitation-inhibition balance differentially gates D1 and D2 accumbens neuron activity.
      ). Consistent with this mechanism, rodent studies in vivo have shown that systemic administration of a short-term dose of selective KOR agonists reduces dopamine levels in mesolimbic and nigrostriatal pathways by acting on presynaptic KORs on dopaminergic neurons. This result was shown with the following selective KOR agonists: U50,488 in the ventral striatum (
      • Di Chiara G.
      • Imperato A.
      Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats.
      ,
      • Manzanares J.
      • Lookingland K.J.
      • Moore K.E.
      Kappa opioid receptor-mediated regulation of dopaminergic neurons in the rat brain.
      ,
      • Devine D.P.
      • Leone P.
      • Pocock D.
      • Wise R.
      Differential involvement of ventral tegmental mu, delta and kappa opioid receptors in modulation of basal mesolimbic dopamine release: In vivo microdialysis studies.
      ,
      • Maisonneuve I.
      • Archer S.
      • Glick S.
      U50, 488, a κ opioid receptor agonist, attenuates cocaine-induced increases in extracellular dopamine in the nucleus accumbens of rats.
      ,
      • Xi Z.-X.
      • Fuller S.A.
      • Stein E.A.
      Dopamine release in the nucleus accumbens during heroin self-administration is modulated by kappa opioid receptors: An in vivo fast-cyclic voltammetry study.
      ) and dorsal striatum (
      • Di Chiara G.
      • Imperato A.
      Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats.
      ,
      • Manzanares J.
      • Lookingland K.J.
      • Moore K.E.
      Kappa opioid receptor-mediated regulation of dopaminergic neurons in the rat brain.
      ), U69,593 in the ventral striatum (
      • Gray A.M.
      • Rawls S.M.
      • Shippenberg T.S.
      • McGinty J.F.
      The K-opioid agonist, U-69593, decreases acute amphetamine-evoked behaviors and calcium-dependent dialysate levels of dopamine and glutamate in the ventral striatum.
      ,
      • Chefer V.I.
      • Bäckman C.M.
      • Gigante E.D.
      • Shippenberg T.S.
      Kappa opioid receptors on dopaminergic neurons are necessary for kappa-mediated place aversion.
      ), spiradoline and enadoline in the dorsal striatum (
      • Zaratin P.
      • Clarke G.D.
      Comparative effects of selective κ-opioid receptor agonists on dopamine levels in the dorsal caudate of freely moving rats.
      ), and salvinorin A in the ventral striatum (
      • Carlezon W.A.
      • Béguin C.
      • DiNieri J.A.
      • Baumann M.H.
      • Richards M.R.
      • Todtenkopf M.S.
      • et al.
      Depressive-like effects of the κ-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats.
      ) and dorsal striatum (
      • Zhang Y.
      • Butelman E.R.
      • Schlussman S.D.
      • Ho A.
      • Kreek M.J.
      Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: Agonist actions at kappa opioid receptors.
      ,
      • Gehrke B.J.
      • Chefer V.I.
      • Shippenberg T.S.
      Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum.
      ) (Figure 1B).
      Figure thumbnail gr1
      Figure 1Kappa opioid receptor (KOR) modulation of dopamine in the cortex and striatum. (A) Normal levels of dopamine at baseline in the ventral and dorsal striatum. (B) Short-term KOR activation lowers dopamine release in the nigrostriatal path. (C) Long-term KOR activation results in higher levels of evoked dopamine release in the mesolimbic and nigrostriatal paths. (D) Normal levels of D2 receptors in the ventral and dorsal striatum. (E) Short-term KOR activation with a D2 agonist lowers dopamine release in the mesolimbic and nigrostriatal paths. (F) Long-term KOR activation with D2 agonists results in acceleration of sensitization of postsynaptic D2 receptors. (G) Normal levels of dopamine at baseline in the cortex. (H) Short-term KOR activation lowers dopamine release in the mesocortical path. (I) Long-term KOR activation results in higher levels of evoked dopamine release in the mesocortical path. MSN, medium spiny neuron.
      It may seem counterintuitive that increased KOR signaling could play a role in the increased striatal dopamine levels seen in schizophrenia, as the direct mechanism of KORs is to lower striatal dopamine levels. However, long-term KOR stimulation has been shown to play a role in increasing the amount of presynaptic dopamine released in both the mesolimbic and nigrostriatal paths in response to stimulus or systemic administration of dopaminergic drugs. Long-term administration of U69,593 increases stimulus- and drug-evoked dopamine levels in both the mesolimbic (
      • Fuentealba J.A.
      • Gysling K.
      • Magendzo K.
      • Andrés M.E.
      Repeated administration of the selective kappa-opioid receptor agonist U-69593 increases stimulated dopamine extracellular levels in the rat nucleus accumbens.
      ,
      • Fuentealba J.A.
      • Gysling K.
      • Andrés M.E.
      Increased locomotor response to amphetamine induced by the repeated administration of the selective kappa-opioid receptor agonist U-69593.
      ,
      • Escobar Adel P.
      • Cornejo F.A.
      • Andrés M.E.
      • Fuentealba J.A.
      Repeated treatment with the kappa opioid receptor agonist U69593 reverses enhanced K (+) induced dopamine release in the nucleus accumbens, but not the expression of locomotor sensitization in amphetamine-sensitized rats.
      ,
      • Heidbreder C.A.
      • Schenk S.
      • Partridge B.
      • Shippenberg T.S.
      Increased responsiveness of mesolimbic and mesostriatal dopamine neurons to cocaine following repeated administration of a selective κ-opioid receptor agonist.
      ) and nigrostriatal (
      • Heidbreder C.A.
      • Schenk S.
      • Partridge B.
      • Shippenberg T.S.
      Increased responsiveness of mesolimbic and mesostriatal dopamine neurons to cocaine following repeated administration of a selective κ-opioid receptor agonist.
      ) paths (Figure 1C). Similarly, long-term administration of salvinorin A leads to increased drug-evoked dopamine levels in the nigrostriatal pathway (
      • Gehrke B.J.
      • Chefer V.I.
      • Shippenberg T.S.
      Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum.
      ). Immediately following long-term administration, basal dopamine levels are unaltered and the ability of a single systemic dose of U69,593 to reduce dopamine levels is preserved, indicating that stimulated increases in dopamine may not be due to KOR desensitization (
      • Escobar A.P.
      • González M.P.
      • Meza R.C.
      • Noches V.
      • Henny P.
      • Gysling K.
      • et al.
      Mechanisms of kappa opioid receptor potentiation of dopamine D2 receptor function in quinpirole-induced locomotor sensitization in ratsKOR potentiation of D2R-induced behavior.
      ,
      • Fuentealba J.A.
      • Gysling K.
      • Magendzo K.
      • Andrés M.E.
      Repeated administration of the selective kappa-opioid receptor agonist U-69593 increases stimulated dopamine extracellular levels in the rat nucleus accumbens.
      ).
      In both the dorsal and ventral striatum, KORs form a complex with the dopamine active transporter (
      • Kivell B.
      • Uzelac Z.
      • Sundaramurthy S.
      • Rajamanickam J.
      • Ewald A.
      • Chefer V.
      • et al.
      Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism.
      ) and with both presynaptic D2 autoreceptors on dopamine terminals of the nigrostriatal and mesolimbic paths, and postsynaptic D2 receptors on medium spiny neurons (MSNs) (
      • Escobar A.P.
      • González M.P.
      • Meza R.C.
      • Noches V.
      • Henny P.
      • Gysling K.
      • et al.
      Mechanisms of kappa opioid receptor potentiation of dopamine D2 receptor function in quinpirole-induced locomotor sensitization in ratsKOR potentiation of D2R-induced behavior.
      ). The increase in stimulus- and drug-evoked dopamine release from both the mesolimbic and nigrostriatal paths following long-term exposure to KOR agonists has been attributed to reduced presynaptic D2 autoreceptor function (
      • Fuentealba J.A.
      • Gysling K.
      • Magendzo K.
      • Andrés M.E.
      Repeated administration of the selective kappa-opioid receptor agonist U-69593 increases stimulated dopamine extracellular levels in the rat nucleus accumbens.
      ).
      Interestingly, KORs have also been shown to interact with postsynaptic D2 receptors on MSNs in ways that may have relevance for schizophrenia. When rodents are exposed to long-term doses of the D2/D3 agonist quinpirole or to drugs that increase dopamine levels, such as amphetamines, they exhibit locomotor sensitization (
      • Szechtman H.
      • Talangbayan H.
      • Eilam D.
      Environmental and behavioral components of sensitization induced by the dopamine agonist quinpirole.
      ), a phenomenon that involves the sensitization of postsynaptic D2 receptors on MSNs (
      • Escobar A.P.
      • González M.P.
      • Meza R.C.
      • Noches V.
      • Henny P.
      • Gysling K.
      • et al.
      Mechanisms of kappa opioid receptor potentiation of dopamine D2 receptor function in quinpirole-induced locomotor sensitization in ratsKOR potentiation of D2R-induced behavior.
      ,
      • Perreault M.L.
      • Graham D.
      • Bisnaire L.
      • Simms J.
      • Hayton S.
      • Szechtman H.
      Kappa-opioid agonist U69593 potentiates locomotor sensitization to the D2/D3 agonist quinpirole: Pre-and postsynaptic mechanisms.
      ,
      • Perreault M.L.
      • Graham D.
      • Scattolon S.
      • Wang Y.
      • Szechtman H.
      • Foster J.A.
      Cotreatment with the kappa opioid agonist U69593 enhances locomotor sensitization to the D2/D3 dopamine agonist quinpirole and alters dopamine D2 receptor and prodynorphin mRNA expression in rats.
      ). Since it was shown that the activity of antipsychotics correlates with their ability to block the D2 receptor (
      • Seeman P.
      • Chau-Wong M.
      • Tedesco J.
      • Wong K.
      Brain receptors for antipsychotic drugs and dopamine: Direct binding assays.
      ,
      • Seeman P.
      • Lee T.
      Antipsychotic drugs: Direct correlation between clinical potency and presynaptic action on dopamine neurons.
      ), increased dopamine signaling through postsynaptic striatal D2 receptors that have become sensitized has been hypothesized to play a critical role in the positive symptoms of schizophrenia (
      • Kapur S.
      • Mamos D.
      Half a century of antipsychotics and still a central role for dopamine D2 receptors.
      ,
      • Kessler R.M.
      • Ansari M.S.
      • Riccardi P.
      • Li R.
      • Jayathilake K.
      • Dawant B.
      • Meltzer H.Y.
      Occupancy of striatal and extrastriatal dopamine D 2 receptors by clozapine and quetiapine.
      ,
      • Seeman P.
      All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2High receptors.
      ,
      • Seeman P.
      Are dopamine D2 receptors out of control in psychosis?.
      ,
      • Seeman M.V.
      • Seeman P.
      Is schizophrenia a dopamine supersensitivity psychotic reaction?.
      ). Importantly, while endogenous levels of KOR signaling do not have an effect on locomotor sensitization (
      • Escobar A.P.
      • González M.P.
      • Meza R.C.
      • Noches V.
      • Henny P.
      • Gysling K.
      • et al.
      Mechanisms of kappa opioid receptor potentiation of dopamine D2 receptor function in quinpirole-induced locomotor sensitization in ratsKOR potentiation of D2R-induced behavior.
      ), administration of KOR agonists resulting in supraphysiological levels of KOR signaling during the sensitization period both accelerate and potentiate this process (
      • Escobar A.P.
      • González M.P.
      • Meza R.C.
      • Noches V.
      • Henny P.
      • Gysling K.
      • et al.
      Mechanisms of kappa opioid receptor potentiation of dopamine D2 receptor function in quinpirole-induced locomotor sensitization in ratsKOR potentiation of D2R-induced behavior.
      ,
      • Perreault M.L.
      • Graham D.
      • Bisnaire L.
      • Simms J.
      • Hayton S.
      • Szechtman H.
      Kappa-opioid agonist U69593 potentiates locomotor sensitization to the D2/D3 agonist quinpirole: Pre-and postsynaptic mechanisms.
      ,
      • Perreault M.L.
      • Graham D.
      • Scattolon S.
      • Wang Y.
      • Szechtman H.
      • Foster J.A.
      Cotreatment with the kappa opioid agonist U69593 enhances locomotor sensitization to the D2/D3 dopamine agonist quinpirole and alters dopamine D2 receptor and prodynorphin mRNA expression in rats.
      ,
      • Perreault M.L.
      • Seeman P.
      • Szechtman H.
      Kappa-opioid receptor stimulation quickens pathogenesis of compulsive checking in the quinpirole sensitization model of obsessive-compulsive disorder (OCD).
      ,
      • Beerepoot P.
      • Lam V.
      • Luu A.
      • Tsoi B.
      • Siebert D.
      • Szechtman H.
      Effects of salvinorin A on locomotor sensitization to D2/D3 dopamine agonist quinpirole.
      ).
      Both the acceleration and potentiation of sensitization are relevant to schizophrenia for two reasons. First, the acceleration of locomotor sensitization has been attributed to the ability of presynaptic KORs to directly increase presynaptic D2 autoreceptor function on dopaminergic terminals where they colocalize, resulting in faster inhibitory responses in presynaptic D2 receptors as measured by fast-scan cyclic voltammetry (
      • Escobar A.P.
      • González M.P.
      • Meza R.C.
      • Noches V.
      • Henny P.
      • Gysling K.
      • et al.
      Mechanisms of kappa opioid receptor potentiation of dopamine D2 receptor function in quinpirole-induced locomotor sensitization in ratsKOR potentiation of D2R-induced behavior.
      ). This change reduces phasic dopamine release, resulting in accelerated sensitization of postsynaptic D2 receptors on MSNs (
      • Escobar A.P.
      • González M.P.
      • Meza R.C.
      • Noches V.
      • Henny P.
      • Gysling K.
      • et al.
      Mechanisms of kappa opioid receptor potentiation of dopamine D2 receptor function in quinpirole-induced locomotor sensitization in ratsKOR potentiation of D2R-induced behavior.
      ) (Figure 1D–F). Second, the potentiation of locomotor sensitization has been attributed to both presynaptic KORs colocalized with D2 autoreceptors and postsynaptic KORs colocalized with D2 receptors on MSNs. In both of these locations, it is hypothesized that KORs increase the efficacy of the D2 receptor signaling (
      • Escobar A.P.
      • González M.P.
      • Meza R.C.
      • Noches V.
      • Henny P.
      • Gysling K.
      • et al.
      Mechanisms of kappa opioid receptor potentiation of dopamine D2 receptor function in quinpirole-induced locomotor sensitization in ratsKOR potentiation of D2R-induced behavior.
      ,
      • Perreault M.L.
      • Graham D.
      • Bisnaire L.
      • Simms J.
      • Hayton S.
      • Szechtman H.
      Kappa-opioid agonist U69593 potentiates locomotor sensitization to the D2/D3 agonist quinpirole: Pre-and postsynaptic mechanisms.
      ). Escobar et al. hypothesized that this increase in efficacy may occur through stabilizing the pre- and postsynaptic D2 receptor or increasing second messenger coupling (
      • Escobar A.P.
      • González M.P.
      • Meza R.C.
      • Noches V.
      • Henny P.
      • Gysling K.
      • et al.
      Mechanisms of kappa opioid receptor potentiation of dopamine D2 receptor function in quinpirole-induced locomotor sensitization in ratsKOR potentiation of D2R-induced behavior.
      ).
      Finally, it has been proposed that the timing of KOR activation and the neural context of elevated dopamine levels play critical roles in the outcome of long-term KOR activation on sensitization (
      • Perreault M.L.
      • Graham D.
      • Bisnaire L.
      • Simms J.
      • Hayton S.
      • Szechtman H.
      Kappa-opioid agonist U69593 potentiates locomotor sensitization to the D2/D3 agonist quinpirole: Pre-and postsynaptic mechanisms.
      ), as it has been shown that KOR activation has the opposite effect on sensitization if KOR agonists are administered sequentially with dopamine agonists rather than simultaneously (
      • Acri J.B.
      • Thompson A.C.
      • Shippenberg T.
      Modulation of pre-and postsynaptic dopamine D2 receptor function by the selective kappa-opioid receptor agonist U69593.
      ,
      • Collins S.L.
      • D'Addario C.
      • Izenwasser S.
      Effects of κ-opioid receptor agonists on long-term cocaine use and dopamine neurotransmission.
      ,
      • Collins S.
      • Gerdes R.
      • D'Addario C.
      • Izenwasser S.
      Kappa opioid agonists alter dopamine markers and cocaine-stimulated locomotor activity.
      ,
      • Shippenberg T.
      • Chefer V.
      • Zapata A.
      • Heidbreder C.A.
      Modulation of the behavioral and neurochemical effects of psychostimulants by κ-opioid receptor systems.
      ). The importance of neural context is further supported by short-term studies of KOR on dopamine release, showing that the effects of U50,488 and salvinorin A on drug- and stimulus-evoked dopamine response shift from inhibition to potentiation depending on the timing of KOR agonist administration relative to that of stimulus (
      • Ehrich J.M.
      • Phillips P.E.
      • Chavkin C.
      Kappa opioid receptor activation potentiates the cocaine-induced increase in evoked dopamine release recorded in vivo in the mouse nucleus accumbens.
      ,
      • Chartoff E.H.
      • Ebner S.R.
      • Sparrow A.
      • Potter D.
      • Baker P.M.
      • Ragozzino M.E.
      • Roitman M.F.
      Relative timing between kappa opioid receptor activation and cocaine determines the impact on reward and dopamine release.
      ).
      In conclusion, we have shown there are several ways in which KORs may contribute to the positive symptoms of schizophrenia. First, long-term overactivation of KORs in the context of the dysregulated dopamine system in schizophrenia may contribute to the increased presynaptic striatal dopamine release by interacting with presynaptic D2 autoreceptors to modulate the response of the dopamine system to various stimuli. Second, although KOR activation has not been shown to result in greater total levels of sensitized postsynaptic D2 receptors (
      • Escobar A.P.
      • González M.P.
      • Meza R.C.
      • Noches V.
      • Henny P.
      • Gysling K.
      • et al.
      Mechanisms of kappa opioid receptor potentiation of dopamine D2 receptor function in quinpirole-induced locomotor sensitization in ratsKOR potentiation of D2R-induced behavior.
      ), the fact that presynaptic KORs accelerate sensitization of postsynaptic D2 receptors and that postsynaptic KORs increase signaling through sensitized postsynaptic D2 receptors has potential relevance to the positive symptoms of schizophrenia. While the mechanisms underlying the therapeutic effects of blocking the D2 receptor and the mechanism of the striatal dopamine excess that are observed in schizophrenia yet unknown, the KOR is uniquely positioned to play a possible role in this pathology.

      A Possible Role for KORs in the Negative and Cognitive Symptoms of Schizophrenia

      Presynaptic activation of KORs on mesocortical projection neurons has been shown to decrease dopamine levels in the medial prefrontal cortex of the rodent, an effect that can be blocked by KOR antagonist nor-binaltorphimine both in vitro (
      • Werling L.
      • Frattali A.
      • Portoghese P.
      • Takemori A.
      • Cox B.
      Kappa receptor regulation of dopamine release from striatum and cortex of rats and guinea pigs.
      ) and in vivo (
      • Tejeda H.A.
      • Counotte D.S.
      • Oh E.
      • Ramamoorthy S.
      • Schultz-Kuszak K.N.
      • Bäckman C.M.
      • et al.
      Prefrontal cortical kappa-opioid receptor modulation of local neurotransmission and conditioned place aversion.
      ). It has also been shown that KOR activation in the medial prefrontal cortex produces conditioned place aversion (
      • Bals-Kubik R.
      • Ableitner A.
      • Herz A.
      • Shippenberg T.S.
      Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats.
      ). Additionally, KOR activation on the soma of mesocortical dopamine projection neurons in in the ventral tegmental area inhibits dopamine release in the medial prefrontal cortex (
      • Margolis E.B.
      • Lock H.
      • Chefer V.I.
      • Shippenberg T.S.
      • Hjelmstad G.O.
      • Fields H.L.
      κ opioids selectively control dopaminergic neurons projecting to the prefrontal cortex.
      ). By decreasing mesocortical dopamine release, a hypothetical overactivation of KORs could play a role in the cortical dopamine deficit observed in patients with schizophrenia. However, the relationship is likely more complex, as long-term treatment with U69,593 increases potassium-stimulated dopamine levels (
      • Fuentealba J.A.
      • Gysling K.
      • Andrés M.E.
      Repeated treatment with the κ-opioid agonist U-69593 increases K+-stimulated dopamine release in the rat medial prefrontal cortex.
      ) (Figure 1F, G).
      Excessive KOR activation could also play a possible role in the cognitive symptoms. Behavioral studies in rodents show that KOR agonists can cause cognitive deficits. The selective KOR agonist U-50488H induces a dose-dependent reduction of prepulse inhibition, which can be restored by the KOR antagonist nor-binaltorphimine and atypical antipsychotic clozapine but not by the typical antipsychotic haloperidol (
      • Bortolato M.
      • Aru G.N.
      • Frau R.
      • Orrù M.
      • Fà M.
      • Manunta M.
      • et al.
      Kappa opioid receptor activation disrupts prepulse inhibition of the acoustic startle in rats.
      ). In contrast, a study using U50,488, U69,593, and salvinorin A did not find any effect on prepulse inhibition (
      • Tejeda H.A.
      • Chefer V.I.
      • Zapata A.
      • Shippenberg T.S.
      The effects of kappa-opioid receptor ligands on prepulse inhibition and CRF-induced prepulse inhibition deficits in the rat.
      ). The KOR agonists U689593, U50488, and GR89,696 all produce impairment of attention as measured by the 5-choice serial reaction-time task, and this disruption can be reversed by naltrexone (
      • Shannon H.E.
      • Eberle E.L.
      • Mitch C.H.
      • McKinzie D.L.
      • Statnick M.A.
      Effects of kappa opioid receptor agonists on attention as assessed by a 5-choice serial reaction time task in rats.
      ). Salvinorin A also causes impairment on the 5-choice serial reaction-time task, an effect that can be blocked by pretreatment with the selective KOR antagonist JDTic (
      • Nemeth C.L.
      • Paine T.A.
      • Rittiner J.E.
      • Béguin C.
      • Carroll F.I.
      • Roth B.L.
      • et al.
      Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats.
      ). Additionally, salvinorin A has been shown to cause cognitive dysfunction and disruption of learning and memory (
      • Braida D.
      • Donzelli A.
      • Martucci R.
      • Capurro V.
      • Sala M.
      Learning and memory impairment induced by salvinorin A, the principal ingredient of Salvia divinorum, in wistar rats.
      ). Most recently, it was shown that U-50488H induced cognitive disruption as measured by the differential reinforcement of low response-rate task, and cognitive deficits could be blocked by the selective KOR antagonist nor-binaltorphimine (
      • Abraham A.D.
      • Fontaine H.M.
      • Song A.J.
      • Andrews M.M.
      • Baird M.A.
      • Kieffer B.L.
      • et al.
      κ-Opioid receptor activation in dopamine neurons disrupts behavioral inhibition.
      ). Finally, selective KOR agonist enadoline (CI-977) (
      • Hunter J.
      • Leighton G.
      • Meecham K.
      • Boyle S.
      • Horwell D.
      • Rees D.
      • Hughes J.
      CI-977, a novel and selective agonist for the κ-opioid receptor.
      ) was shown to induce cognitive impairment in rhesus monkeys on the continuous performance task (
      • Davis R.E.
      • Callahan M.J.
      • Dickerson M.
      • Downs D.A.
      Pharmacologic activity of CI-977, a selective kappa opioid agonist, in rhesus monkeys.
      ). It is important to note that this result may depend on the state of the system, as both enadoline and U50488 have been shown to have short-term neuroprotective effects in animals if administered immediately prior to the onset of ischemic brain damage (
      • Kusumoto K.
      • Mackay K.B.
      • McCulloch J.
      The effect of the kappa-opioid receptor agonist CI-977 in a rat model of focal cerebral ischaemia.
      ,
      • Mackay K.B.
      • Kusumoto K.
      • Graham D.I.
      • McCulloch J.
      Effect of the kappa-1 opioid agonist CI-977 on ischemic brain damage and cerebral blood flow after middle cerebral artery occlusion in the rat.
      ,
      • Hayward N.J.
      • McKnight A.T.
      • Woodruff G.N.
      Neuroprotective effect of the χ-agonist enadoline (CI-977) in rat models of focal cerebral ischaemia.
      ,
      • Mackay K.B.
      • Kusumoto K.
      • Graham D.I.
      • McCulloch J.
      Focal cerebral ischemia in the cat: Pretreatment with a kappa-1 opioid receptor agonist, CI-977.
      ,
      • Hiramatsu M.
      • Hyodo T.
      • Kameyama T.
      U-50488H, a selective κ-opioid receptor agonist, improves carbon monoxide-induced delayed amnesia in mice.
      ).
      Ultimately, the complete mechanism underlying the positive and negative symptoms of schizophrenia may likely involve contributions from other brain regions and neurotransmitter systems. KORs also modulate glutamate neurotransmission in the ventral tegmental area (
      • Margolis E.B.
      • Hjelmstad G.O.
      • Bonci A.
      • Fields H.L.
      Both kappa and mu opioid agonists inhibit glutamatergic input to ventral tegmental area neurons.
      ) and are present throughout diverse brain regions that have been implicated in the pathology of schizophrenia, including the hippocampus, locus coeruleus, hypothalamus, and amygdala. For a comprehensive review of KORs in other brain regions, see previous reports (
      • Tejeda H.A.
      • Bonci A.
      Dynorphin/kappa-opioid receptor control of dopamine dynamics: Implications for negative affective states and psychiatric disorders.
      ,
      • Crowley N.A.
      • Kash T.L.
      Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment.
      ,
      • Tejeda H.
      • Shippenberg T.
      • Henriksson R.
      The dynorphin/κ-opioid receptor system and its role in psychiatric disorders.
      ).

      Histological Studies in Patients With Schizophrenia Have Shown Abnormalities in the Dynorphin/KOR System

      The evidence for elevated levels of dynorphin or other endorphins is mixed. Heikkilä et al. (
      • Heikkilä L.
      • Rimón R.
      • Ternius L.
      Dynorphin A and substance P in the cerebrospinal fluid of schizophrenic patients.
      ) found that elevated levels of dynorphin in the cerebrospinal fluid of patients with schizophrenia compared with that in healthy controls correlated with worsening BPRS scores. In another, larger study of 120 hospitalized patients with schizophrenia, Lindström et al. (
      • Lindström L.H.
      Clinical and biological markers for outcome in schizophrenia: A review of a longitudinal follow-up study in Uppsala schizophrenia research project.
      ) found that elevated dynorphin levels were predicative of worse disease outcomes. Another study of 35 patients with schizophrenia found lower levels of dynorphin in the cerebrospinal fluid; however, the comparison group was patients with various neurologic diseases, including tumors, rather than healthy control subjects (
      • Zhang A.
      • Zhou G.
      • Xi G.
      • Gu N.
      • Xia Z.
      • Yao J.
      • et al.
      Lower CSF level of dynorphin (1–8) immunoreactivity in schizophrenic patients.
      ). In addition to dynorphin studies, there have been other studies showing increased beta-endorphin levels (
      • Lindtröm L.
      • Winderlöv E.
      • Gunne L.M.
      • Wahlström A.
      • Terenius L.
      Endorphins in human cerebrospinal fluid: clinical correlations to some psychotic states.
      ,
      • Domschke W.
      • Dickschas A.
      • Mitznegg P.
      CSF β-endorphin in schizophrenia.
      ,
      • Lindström L.H.
      • Besev G.
      • Gunne L.M.
      • Terenius L.
      CSF levels of receptor-active endorphins in schizophrenic patients: Correlations with symptomalogy and monoamine metabolites.
      ). In contrast, another study did not replicate these findings (
      • Ross M.
      • Berger P.A.
      • Goldstein A.
      Plasma beta-endorphin immunoreactivity in schizophrenia.
      ).
      In a limited postmortem study of 4 patients and 4 controls, Royston et al. (
      • Royston M.
      • Slater P.
      • Simpson M.
      • Deakin J.
      Analysis of laminar distribution of kappa opiate receptor in human cortex: comparison between schizophrenia and normal.
      ) found that the KOR distribution in the parahippocampal gyrus of patients with schizophrenia was significantly different from that in control participants, although the significance of this finding is unclear. In a postmortem study of both patients with schizophrenia and patients with bipolar disorder, Peckys and Hurd (
      • Peckys D.
      • Hurd Y.
      Prodynorphin and κ opioid receptor mRNA expression in the cingulate and prefrontal cortices of subjects diagnosed with schizophrenia or affective disorders.
      ) did not find any significant difference in the expression of prodynorphin and KOR messenger RNA in the frontal cortex.

      Conclusions

      In conclusion, while there are several generations of antipsychotic drugs that are effective for treating the positive symptoms of schizophrenia, not all patients fully respond to the antipsychotics with safer clinical profiles. Clozapine, the most effective antipsychotic and drug of last resort for many nonresponders, is often not prescribed because of fear of side effects. Additionally, there are currently no effective treatments for the negative or cognitive symptoms (
      • Sarkar S.
      • Hillner K.
      • Velligan D.I.
      Conceptualization and treatment of negative symptoms in schizophrenia.
      ). There is a need to examine novel targets to find effective treatments for the negative and cognitive symptoms, as well as to find safer and more effective treatments for the positive symptoms for nonresponders. This review shows that the KOR may be a reasonable new therapeutic target to investigate further, and we hope that our review will provide support for additional studies targeting this mechanism for the treatment of positive and negative symptoms in schizophrenia.

      Acknowledgments and Disclosures

      SDC receives compensation from employment by Terran Biosciences and also has patents and stock ownership in Terran Biosciences. AA-D has received stock options in Terran Biosciences.

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      • Role of Kappa Opioid Receptors in Symptoms of Schizophrenia: What Is the Neurobiology?
        Biological PsychiatryVol. 86Issue 7
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          The opioid peptide–containing neurons comprise a neuromodulatory system that is widespread across the central nervous system with three classical cognate receptors (mu, delta, and kappa subtypes), all with their preferred endogenous peptide ligands. The kappa opioid receptors (KORs) have the strongest affinity for the endogenous ligand dynorphin (1) and demonstrate specific distribution patterns, concentrated along the spinal nociceptive pathways, brainstem, striatum, subcortical limbic regions, and cortex.
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