The AAPS Journal

, Volume 7, Issue 3, pp E592–E599 | Cite as

k Opioids as potential treatments for stimulant dependence

  • Thomas E. PrisinzanoEmail author
  • Kevin Tidgewell
  • Wayne W. Harding


Stimulant abuse is a major problem in the United States and the development of pharmacological treatments for stimulant abuse remains an important therapeutic goal. Classically, the “dopamine hypothesis” has been used to explain the development of addiction and dependence of stimulants. This hypothesis involves the direct increase of dopamine as the major factor in mediating the abuse effects. Therefore, most treatments have focused on directly influencing the dopamine system. Another approach, which has been explored for potential treatments of stimulant abuse, is the use of κ opioid agonists. The κ receptor is known to be involved, via indirect effects, in synaptic dopamine levels. This review covers several classes of κ opioid ligands that have been explored for this purpose.


kappa opioid self-administration stimulant 


  1. 1.
    Cami J, Ferre M. Drug addiction.N Engl J Med. 2003;349:975–986.PubMedCrossRefGoogle Scholar
  2. 2.
    Nestler EJ. Molecular basis of long-term plasticity underlying addiction.Nat Rev Neurosci. 2001;2:119–128.PubMedCrossRefGoogle Scholar
  3. 3.
    Mitscher LA, Baker W. Tuberculosis: a search for novel therapy starting with natural products.Med Res Rev. 1998;18:363–374.PubMedCrossRefGoogle Scholar
  4. 4.
    McCoy CB, Inciardi JA.Sex, Drugs, and the Continuing, Spread of AIDS. Los Angeles: Roxbury Publishing Co; 1995.Google Scholar
  5. 5.
    National Drug Intelligence Center.National Drug Threat Assessment 2004. Washington, DC: US Department of Justice; 2004.Google Scholar
  6. 6.
    Howell LL, Wilcox KM. The dopamine transporter and cocaine medication development: drug self-administration, in nonhuman primates.J Pharmacol Exp Ther. 2001;298:1–6.PubMedGoogle Scholar
  7. 7.
    National DI.C. National Drug Threat, Assessment. Johnston, PA: US Department of Justice; 2001.Google Scholar
  8. 8.
    Anglin MD, Burke C, Perrochet B, Stamper E, Dawud-Noursi S. History of the methamphetamine problem.J Psychoactive Drugs. 2000;32:137–141.PubMedGoogle Scholar
  9. 9.
    Rawson RA, Anglin MD, Ling W. Will the methamphetamine problem go away?.J Addict Dis. 2002;21:5–19.PubMedCrossRefGoogle Scholar
  10. 10.
    Rood L. 2005.Google Scholar
  11. 11.
    Carroll FI, Howell LL, Kuhar, MJ. Pharmacotherapies for treatment of cocaine abuse preclinical aspects.J Med Chem. 1999;42:2721–2736.PubMedCrossRefGoogle Scholar
  12. 12.
    Kuhar MJ, Ritz MC, Boja JW. The dopamine hypothesis of the reinforcing properties of cocaine.Trends Neurosci. 1991;14:299–302.PubMedCrossRefGoogle Scholar
  13. 13.
    Koob GF, Bloom FE. Cellular and molecular mechanisms of drug dependence.Science. 1988;242:715–723.PubMedCrossRefGoogle Scholar
  14. 14.
    Robinson TE, Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction.Brain Res Brain Res Rev. 1993;18:247–291.PubMedCrossRefGoogle Scholar
  15. 15.
    Kuhar MJ, Pilotte NS. Neurochemical changes in cocaine withdrawal.Trends Pharmacol Sci. 1996;17:260–264.PubMedCrossRefGoogle Scholar
  16. 16.
    Callahan PM, Cunningham KA. Modulation of the discriminative stimulus properties of cocaine: comparison of the effects of fluoxetine with 5-HT1A and 5-HT1B receptor, agonists.Neuropharmacology. 1997;36:373–381.PubMedCrossRefGoogle Scholar
  17. 17.
    Callahan PM, Cunningham KA. Modulation of the discriminative stimulus properties of cocaine by 5-HT1B and 5-HT2C receptors.J Pharmacol Exp Ther. 1995;274:1414–1424.PubMedGoogle Scholar
  18. 18.
    McMahon LR, Cunningham KA. Antagonism of 5-Hydroxytryptamine2A receptors attenuates the behavioral effects of cocaine in rats.J Pharmacol Exp Ther. 2001;297:357–363.PubMedGoogle Scholar
  19. 19.
    Kelley AE, Lang CG. Effects of GBR 12909, a selective dopamine uptake inhibitor, on motor activity and operant behavior in the rat.Eur J Pharmacol. 1989;167:385–395.PubMedCrossRefGoogle Scholar
  20. 20.
    Carroll FI, Kotian P, Dehghani A, et al. Cocaine and 3β-(4′-Substituted phenyl)tropane-2β-carboxylic acid ester and amide analogues. New high-affinity and selective compounds for the dopamine transporter.J Med Chem. 1995;38:379–388.PubMedCrossRefGoogle Scholar
  21. 21.
    Belej T, Manji D, Sioutis S, Barros HM, Nobrega JN. Changes in serotonin and norepinephrine uptake sites after chronic cocaine: pre- vs post-withdrawal effects.Brain Res. 1996;736:287–296.PubMedCrossRefGoogle Scholar
  22. 22.
    Sora I, Hall FS, Andrews AM, et al. MOlecular mechanisms of cocaine reward. Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference.Proc Natl Acad Sci USA. 2001;98:5300–5305.PubMedCrossRefGoogle Scholar
  23. 23.
    Baumann MH, Rothman RB. Alterations in serotonergic responsiveness during cocaine withdrawal in rats: similarities to major depression in humans.Biol Psychiatry. 1998;44:578–591.PubMedCrossRefGoogle Scholar
  24. 24.
    Rothman RB, Baumann MH, Dersch CM, et al. Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin.Synapse. 2001;39:32–41.PubMedCrossRefGoogle Scholar
  25. 25.
    Kulkarni SS, Newman AH, Houlihan WJ. Three-dimensional quantitative structure-activity relationships of mazindol analogues at the dopamine transporter.J Med Chem. 2002;45:4119–4127.PubMedCrossRefGoogle Scholar
  26. 26.
    Kreek MJ, LaForge KS, Butelman E. Pharmacotherapy of addictions.Nat Rev Drug Discov. 2002;1:710–726.PubMedCrossRefGoogle Scholar
  27. 27.
    Prisinzano T, Rice KC, Baumann MH, Rothman RB. Development of neurochemical normalization (“agonist substitution”) therapeutics for stimulant, abuse: focus on the dopamine uptake inhibitor, GBR 12909.Curr Med Chem CNS Agents. 2004;4:47–59.Google Scholar
  28. 28.
    Grabowski J, Shearer J, Merrill J, Negus SS. Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence.Addict Behav. 2004;29:1439–1464.PubMedCrossRefGoogle Scholar
  29. 29.
    Mello NK, Negus SS. Interactions between kappa opioid, agonists and cocaine. Preclinical studies.Ann N Y Acad Sci. 2000;909:104–132.PubMedCrossRefGoogle Scholar
  30. 30.
    Shippenberg TS, Chefer VI, Zapata A, Heidbreder CA. Modulation of the behavioral and neurochemical effects of psychostimulants by kappa-opioid receptor systems.Ann NY Acad Sci. 2001;937:50–73.PubMedCrossRefGoogle Scholar
  31. 31.
    Collins SL, Kunko PM, Ladenheim B, et al. Chronic cocaine increases kappa-opioid receptor density: lack of effect by selective dopamine uptake inhibitors.Synapse. 2002;45:153–158.PubMedCrossRefGoogle Scholar
  32. 32.
    Tzaferis JA, McGinty JF. Kappa opioid receptor stimulation decreases amphetamine-induced behavior and neuropeptide mRNA expression in the striatum.Brain Res Mol Brain Res. 2001;93:27–35.PubMedCrossRefGoogle Scholar
  33. 33.
    McCarthy L, Wetzel M, Sliker JK, Eisenstein TK, Rogers TJ. Opioids, opioid receptors, and the immune response.Drug Alcohol Depend. 2001;62:111–123.PubMedCrossRefGoogle Scholar
  34. 34.
    Chao CC, Gekker G, Hu S, et al. Kappa opioid receptors in human microglia downregulate human immunodeficiency virus 1 expression.Proc, Natl Acad Sci USA. 1996;93:8051–8056.CrossRefGoogle Scholar
  35. 35.
    Peterson PK, Gekker G, Lokensgard JR, et al. Kappa opioid receptor agonist suppression of HIV-1 expression in CD4+ lymphocytes.Biochem Pharmacol. 2001;61: 1145–1151.PubMedCrossRefGoogle Scholar
  36. 36.
    Gekker G., Hu S, Wentland MP, et al. κ-Opioid receptor ligands inhibit cocaine-induced HIV-1 expression in microglial cells.J Pharmacol Exp Ther. 2004;309:600–606.PubMedCrossRefGoogle Scholar
  37. 37.
    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.J Pharmacol Exp Ther. 1988;246:282–286.PubMedGoogle Scholar
  38. 38.
    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.J Pharmacol Exp Ther. 1988;244:1067–1080.PubMedGoogle Scholar
  39. 39.
    Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.Proc Natl Acad Sci USA. 1988;85:5274–5278.PubMedCrossRefGoogle Scholar
  40. 40.
    Spanagel R, Herz A, Shippenberg TS. The effects of opioid, peptides on dopamine release in the nucleus accumbens: an in vivo microdialysis study.J Neurochem. 1990;55:1734–1740.PubMedCrossRefGoogle Scholar
  41. 41.
    Spanagel R, Herz A, Shippenberg T. Opposing tonically active endogenous opioid, systems modulate the mesolimbic dopaminergic pathway.Proc Natl Acad Sci USA. 1992;89:2046–2050.PubMedCrossRefGoogle Scholar
  42. 42.
    Jackisch R, Hotz H, Hertting G. No evidence for presynaptic opioid receptors on cholinergic, but presence of kappa-receptors on dopaminergic neurons in the rabbit caudate nucleus: involvement of endogenous opioids.Naunyn Schmiedebergs Arch Pharmacol. 1993;348:234–241.PubMedCrossRefGoogle Scholar
  43. 43.
    Margolis EB, Hjelmstad GO, Bonci A, Fields HL. κ-Opioid agonists directly inhibit midbrain dopaminergic neurons.J Neurosci. 2003;23:9981–9986.PubMedGoogle Scholar
  44. 44.
    Suzuki T, Kishimoto Y, Ozaki S, Narita M. Mechanism of opioid dependence and interaction between opioid receptors.Eur J Pain. 2001;5:63–65.PubMedCrossRefGoogle Scholar
  45. 45.
    Thompson AC Jr, Zapata A, Jr, Justice JB Jr, et al. κ-Opioid receptor activation modifies dopamine uptake in the nucleus accumbens and opposes the effects of cocaine.J Neurosci. 2000;20:9333–9340.PubMedGoogle Scholar
  46. 46.
    Izenwasser S, French D, Carroll FI, Funko PM. Continuous infusion of selective dopamine uptake inhibitors or cocaine produces time-dependent changes in rat locomotor activity.Behav Brain Res. 1999;99:201–208.PubMedCrossRefGoogle Scholar
  47. 47.
    Acri JB, Thompson AC, Shippenberg T. Modulation of pre- and postsynaptic dopamine D2 receptor function by the selective kappaopioid receptor agonist U 69593.Synapse. 2001;39:343–350.PubMedCrossRefGoogle Scholar
  48. 48.
    Heidbreder CA, Schenk S, Partridge B, Shippenberg TS. Increased responsiveness of mesolimbic and mesostriatal dopamine neurons to cocaine following repeated administration of a selective kappa-opioid receptor agonist.Synapse. 1998;30:255–262.PubMedCrossRefGoogle Scholar
  49. 49.
    Collins SL, Gerdes RM, D’Addario C, Izenwasser S. Kappa opioid agonists alter dopamine markers and cocaine-stimulated locomotor activity.Behav Pharmacol. 2001;12:237–245.PubMedGoogle Scholar
  50. 50.
    Collins SL, D’Addario C, Izenwasser S. Effects of κ-opioid receptor agonists on long-term cocaine use and dopamine neurotransmission.Eur J Pharmacol. 2001;426:25–34.PubMedCrossRefGoogle Scholar
  51. 51.
    Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ. Effect of the kappa opioid agonist R-84760 on cocaine-induced increases in striatal dopamine levels and cocaine-induced place preference in C57BL/6J mice.Psychopharmacology (Berl). 2004;173:146–152.CrossRefGoogle Scholar
  52. 52.
    Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ. Effect of the endogenous κ opioid agonist dynorphim A(1–17) on cocaine-evoked increases in striatal dopamine levels and cocaine-induced place preference in C57BL/6J mice.Psychopharmacology (Berl). 2004;172:422–429.CrossRefGoogle Scholar
  53. 53.
    Schenk S, Partridge B, Shippenberg TS. Reinstatement of extinguished drug-taking behavior in rats: effect of the kappa-opioid receptor agonist, U69593.Psychopharmacology (Berl). 2000;151:85–90.CrossRefGoogle Scholar
  54. 54.
    Neumeyer JL, Gu XH, van Vliet LA, et al. Mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine abuse: synthesis and opioid receptor binding affinity of N-substituted derivatives of morphinan.Bioorg Med Chem Lett. 2001;11:2735–2740.PubMedCrossRefGoogle Scholar
  55. 55.
    Zukin RS, Eghbali M, Olive D, Unterwald EM, Tempel A. Characterization and visualization of rat and guinea pig brain kappa opioid receptors: evidence for kappa, 1 and kappa 2 opioid receptors.Proc Natl Acad Sci USA. 1988;85:4061–4065.PubMedCrossRefGoogle Scholar
  56. 56.
    Butelman ER, Ko MC, Sobczyk-Kojiro K, et al. kappa-Opioid receptor binding populations in rhesus monkey brain: relationship to an assay of thermal antinociception.J Pharmacol Exp Ther. 1998;285:595–601.PubMedGoogle Scholar
  57. 57.
    Caudle RM, Finegold AA, Mannes AJ, et al. Spinal kappa1 and kappa2 opioid binding sites in rats, guinea pigs, monkeys and humans.Neuroreport. 1998;9:2523–2525.PubMedCrossRefGoogle Scholar
  58. 58.
    Wollemann M, Benyhe S, Simon J. The kappa-opioid receptor: evidence for the different subtypes.Life Sci. 1993;52:599–611.PubMedCrossRefGoogle Scholar
  59. 59.
    Ni Q, Xu H, Partilla JS, et al. Selective labeling of {ieE597-1} opioid receptors in rat brain by [125I]IOXY: interaction of opioid peptides and other drugs with multiple {ieE597-2} binding sites.Peptides. 1993;14:1279–1293.PubMedCrossRefGoogle Scholar
  60. 60.
    Rothman RB, Bykov V, Xue BG, et al. Interaction of opioid peptides and other drugs with multiple kappa receptors in rat and human brain. Evidence for species differences.Peptides. 1992;13:977–987.PubMedCrossRefGoogle Scholar
  61. 61.
    Lahti RA, Mickelson MM, McCall JM, Von Voigtlander PF. [3H]U-69593 a highly selective ligand for the opioid kappa receptor.Eur J Pharmacol. 1985;109:281–284.PubMedCrossRefGoogle Scholar
  62. 62.
    Romer D, Buscher H, Hill RC, et al. Bremazocine: a potent, longacting opiate kappa-agonist.Life Sci. 1980;27:971–978.PubMedCrossRefGoogle Scholar
  63. 63.
    Portoghese PS, Lipkowski AW, Takemori AE. Binaltorphimine and nor-binaltorphimine, potent and selective kappa-opioid receptor antagonists.Life Sci. 1987;40:1287–1292.PubMedCrossRefGoogle Scholar
  64. 64.
    Portoghese PS, Garzon-Aburbeh A, Nagase H, Lin CE, Takemori AE. Role of the spacer in conferring kappa opioid receptor selectivity to bivalent ligands related to norbinaltorphimine.J Med Chem. 1991;34:1292–1296.PubMedCrossRefGoogle Scholar
  65. 65.
    Clark JA, Liu L, Price M, et al. Kappa opiate receptor multiplicity: evidence for two U50,488-sensitive kappa1 subtypes and a novel kappa3, subtype.J Pharmacol Exp Ther. 1989;251:461–468.PubMedGoogle Scholar
  66. 66.
    Raynor K, Kong H, Chen Y, et al. Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors.Mol Pharmacol. 1994;45:330–334.PubMedGoogle Scholar
  67. 67.
    Rusovici DE, Negus SS, Mello NK, Bidlack JM. Kappa-opioid receptors are differentially labeled by arylacetamides and benzomorphans.Eur J Pharmacol. 2004;485:119–125.PubMedCrossRefGoogle Scholar
  68. 68.
    Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L. Dynorphin-(1–13), an extraordinarily potent opioid peptide.Proc Natl Acad Sci USA. 1979;76:6666–6670.PubMedCrossRefGoogle Scholar
  69. 69.
    Chavkin C, James IF, Goldstein A. Dynorphin is a specific endogenous ligand of the kappa opioid receptor.Science: 1982;215:413–415.PubMedCrossRefGoogle Scholar
  70. 70.
    Casy AF, Parfitt RT.Opioid Analgesics: Chemistry and Receptors. New York: Plenum Press; 1986.Google Scholar
  71. 71.
    Eguchi M. Recent advances in selective opioid receptor agonists and antagonists.Med Res Rev. 2004;24:182–212.PubMedCrossRefGoogle Scholar
  72. 72.
    Archer S, Glick SD, Bidlack JM. Cyclazocine revisited.Neurochem Res. 1996;21:1369–1373.PubMedCrossRefGoogle Scholar
  73. 73.
    Glick SD, Visker KE, Maisonneuve IM. Effects of cyclazocine on cocaine self-administration in rats.Eur J Pharmacol. 1998;357:9–14.PubMedCrossRefGoogle Scholar
  74. 74.
    Maisonneuve IM, Glick SD. (+/-)Cyclazocine blocks the dopamine response to nicotine.Neuroreport. 1999;10:693–696.PubMedCrossRefGoogle Scholar
  75. 75.
    Preston KL, Umbricht A, Schroeder JR, et al. Cyclazocine: comparison to hydromorphone and interaction with cocaine.Behav Pharmacol. 2004;15:91–102.PubMedCrossRefGoogle Scholar
  76. 76.
    Cosgrove KP, Carroll ME. Effects of bremazocine on self-administration of smoked cocaine base and orally delivered ethanol, phencyclidine, saccharin, and food in rhesus monkeys: a behavioral economic analysis.J Pharmacol Exp Ther. 2002;301:993–1002.PubMedCrossRefGoogle Scholar
  77. 77.
    Nestby P, Schoffelmeer AN, Homberg JR, et al. Bremazocine reduces unrestricted free-choice ethanol self-administration in rats without affecting sucrose preference.Psychopharmacology (Berl). 1999;142:309–317.CrossRefGoogle Scholar
  78. 78.
    Wentland MP, Lou R, Ye Y, et al. 8-Carboxamidocyclazocine analogues: redefining the structure-activity relationships of 2, 6-methano-3-benzazocines.Bioorg Med Chem Lett. 2001;11:623–626.PubMedCrossRefGoogle Scholar
  79. 79.
    Bidlack JM, Cohen DJ, McLaughlin JP, et al. 8-Carboxamidocyclazocine: a long-acting, novel benzomorphan.J Pharmacol Exp Ther. 2002;302:374–380.PubMedCrossRefGoogle Scholar
  80. 80.
    Stevenson GW, Wentland MP, Bidlack JM, Mello NK, Negus SS. Effects of the mixed-action kappa/mu opioid agonist 8-carboxamidocyclazocine on cocaine- and food-maintained responding in rhesus monkeys.Eur J Pharmacol. 2004;506:133–141.PubMedCrossRefGoogle Scholar
  81. 81.
    Bowen CA, Negus SS, Zong R, et al. Effects of mixed-action kappa/mu opioids on cocaine self-administration and cocaine discrimination by rhesus monkeys.Neuropsychopharmacology. 2003;28:1125–1139.PubMedGoogle Scholar
  82. 82.
    Szmuszkovicz J, von Voigtlander PF. Benzeneacetamide amines: structurally novel non-mμ opioids.J Med Chem. 1982;25:1125–1126.PubMedCrossRefGoogle Scholar
  83. 83.
    Szmuszkovicz J. U-50,488 and the kappa receptor: a personalized account covering the period 1973 to 1990.Prog Drug Res. 1999;52:167–195.PubMedGoogle Scholar
  84. 84.
    Szmuszkovicz J. U-50,488 and the kappa receptor. Part II: 1991–1998.Prog Drug Res. 1999;53:1–51.PubMedGoogle Scholar
  85. 85.
    Maisonneuve IM, Archer S, Glick SD. U50,488, a kappa opioid receptor agonist, attenuates cocaine-induced increases in extracellular dopamine in the nucleus accumbens of rats.Neurosci Lett. 1994;181:57–60.PubMedCrossRefGoogle Scholar
  86. 86.
    Broadbent J, Gaspard TM, Dworkin SI. Assessment of the discriminative stimulus effects of cocaine in the rat: lack of interaction with opioids.Pharmacol Biochem Behav. 1995;51:379–385.PubMedCrossRefGoogle Scholar
  87. 87.
    Glick SD, Maisonneuve IM, Raucci J, Archer S. Kappa opioid inhibition of morphine and cocaine self-administration in rats.Brain Res. 1995;681:147–152.PubMedCrossRefGoogle Scholar
  88. 88.
    Kuzmin AV, Semenova S, Gerrits MA, Zvartan EE, Van Ree JM. Kappa-opioid receptor agonist U50,488H modulates cocaine and morphine self-administration in drug-naive rats and mice.Eur J Pharmacol. 1997;321:265–271.PubMedCrossRefGoogle Scholar
  89. 89.
    Kantak KM, Riberdy A, Spealman RD. Cocaine-opioid interactions in groups of rats trained to discriminate different doses of cocaine.Psychopharmacology (Berl). 1999;147:257–265.CrossRefGoogle Scholar
  90. 90.
    Negus SS, Mello NK, Portoghese PS, Lin C-E. Effects ofkappa opioids on cocaine self-administration by rhesus monkeys.J Pharmacol Exp Ther. 1997;282:44–55.PubMedGoogle Scholar
  91. 91.
    Negus SS, Mello NK. Effects of kappa opioid agonists on the discriminative stimulus effects of cocaine in rhesus monkeys.Exp Clin Psychopharmacol. 1999;7:307–317.PubMedCrossRefGoogle Scholar
  92. 92.
    Negus SS. Effects of the kappa opioid agonist U50,488 and the kappa opioid antagonist nor-binaltorphimine on choice between cocaine and food in rhesus monkeys.Psychopharmacology (Berl). 2004;176:204–213.CrossRefGoogle Scholar
  93. 93.
    Schenk S, Partridge B, Shippenberg TS. U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking.Psychopharmacology (Berl). 1999;144:339–346.CrossRefGoogle Scholar
  94. 94.
    Vanderschuren LJ, Schoffelmeer AN, Wardeh G, De Vries TJ. Dissociable effects of the kappa-opioid receptor agonists bremazocine, U69593, and U50488H on locomotor activity and long-term behavioral sensitization induced by amphetamine and cocaine.Psychopharmacology (Berl). 2000;150:35–44.CrossRefGoogle Scholar
  95. 95.
    El Daly E, Chefer V, Sandill S, Shippenberg TS. Modulation of the neurotoxic effects of methamphetamine by the selective κ opioid receptor agonist U69593.J Neurochem. 2000;74:1553–1562.PubMedCrossRefGoogle Scholar
  96. 96.
    Powell KR, Holtzman SG. Modulation of the discriminative stimulus effects of d-amphetamine by mu and kappa opioids in squirrel monkeys.Pharmacol Biochem Behav. 2000;65:43–51.PubMedCrossRefGoogle Scholar
  97. 97.
    Sorbera L, Castaner J, Leeson P. Nalfurafine hydrochloride. Antipruritic, analgesic, kappa opioid agonist.Drugs of the Future. 2003;28:237–242.CrossRefGoogle Scholar
  98. 98.
    Nagase H, Hayakawa J, Kawamura K, et al. Discovery of a structurally novel opioid κ-agonist derived from 4,5-epoxymorphinan.Chem Pharm Bull (Tokyo). 1998;46:366–369.Google Scholar
  99. 99.
    Wang Y, Tang K, Inan S, et al. Comparison of pharmacological activities of three distinet κ-ligands (Salvinorin A, TRK-820 and 3 FLB) on κ opioid receptors in vitro and their antipruritic and antinociceptive activities in vivo.J Pharmacol Exp Ther. 2004;312:220–230.PubMedCrossRefGoogle Scholar
  100. 100.
    Endoh T, Tajima A, Izumimoto N, et al. TRK-820, a selective κ-opioid agonist, produces potent antinociception in cynomolgus monkeys.Jpn J Pharmacol. 2001;85:282–290.PubMedCrossRefGoogle Scholar
  101. 101.
    Endoh T, Matsuura H, Tajima A, et al. Potent antinociceptive effects of TRK-820, a novel κ-opioid receptor agonist.Life Sci. 1999;65:1685–1694.PubMedCrossRefGoogle Scholar
  102. 102.
    Endoh T, Tajima A, Suzuki T, et al. Characterization of the antinociceptive effects of TRK-820 in the rat.Eur J Pharmacol. 2000;387:133–140.PubMedCrossRefGoogle Scholar
  103. 103.
    Suzuki T, Izumimoto N, Takezawa Y, et al. Effect of repeated administration of TRK-820, a κ-opioid receptor agonist, on tolerance to its antinociceptive and sedative actions.Brain Res. 2004;995:167–175.PubMedCrossRefGoogle Scholar
  104. 104.
    Mori T, Nomura M, Nagase H, Narita M, Suzuki T. Effects of a newly synthesized κ-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats.Psychopharmacology (Berl). 2002;161:17–22.CrossRefGoogle Scholar
  105. 105.
    Hasebe K, Kawai K, Suzuki T, et al. Possible pharmacotherapy of the opioid κ receptor agonist for drug dependence.Ann NY Acad Sci. 2004;1025:404–413.PubMedCrossRefGoogle Scholar
  106. 106.
    Mori T, Nomura M, Yoshizawa K, et al. Differential properties between TRK-820 and U-50,488H on the discriminative stimulus effects in rats.Life Sci. 2004;75:2473–2482.PubMedCrossRefGoogle Scholar
  107. 107.
    Levi MS, Borne RF. A review of chemical agents in the pharmacotherapy of addiction.Curr Med Chem. 2002;9:1807–1818.PubMedGoogle Scholar
  108. 108.
    Mash DC, Kovera CA, Pablo J, et al. Ibogaine: complex pharmacokinetics, concerns for safety, and preliminary efficacy measures.Ann NY Acad Sci. 2000;914:394–401.PubMedCrossRefGoogle Scholar
  109. 109.
    Mash DC, Kovera CA, Buck BE, et al. Medication development of ibogaine as a pharmacotherapy for drug dependence.Ann NY Acad Sci. 1998;844:274–292.PubMedCrossRefGoogle Scholar
  110. 110.
    Baumann MH, Pablo JP, Ali SF, Rothman RB, Mash DC. Noribogaine (12-hydroxyibogamine): a biologically active metabolite of the antiaddictive drug ibogaine.Ann NY Acad Sci. 2000;914:354–368.PubMedCrossRefGoogle Scholar
  111. 111.
    Baumann MH, Rothman RB, Pablo JP, Mash DC. In vivo neurobiological effects of ibogaine and its O-desmethyl metabolite, 12-hydroxyibogamine (noribogaine), in rats.J Pharmacol Exp Ther. 2001;297:531–539.PubMedGoogle Scholar
  112. 112.
    Sweetnam PM, Lancaster J, Snowman A, et al. Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine’s putative anti-addictive activity.Psychopharmacology (Berl). 1995;118:369–376.CrossRefGoogle Scholar
  113. 113.
    He D-Y, McGough NNH, Ravindranathan A, et al. Glial cell line-derived neúrotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption.J Neurosci. 2005;25:619–628.PubMedCrossRefGoogle Scholar
  114. 114.
    Leal MB, Michelin K, Souza DO, Elisabetsky E. Ibogaine attenuation of morphine withdrawal in mice: role of glutamate N-methyl-aspartate receptors.Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:781–785.PubMedCrossRefGoogle Scholar
  115. 115.
    Glick SD, Maisonneuve IS. Mechanisms of antiaddictive actions of ibogaine.Ann N Y Acad Sci. 1998;844:214–226.PubMedCrossRefGoogle Scholar
  116. 116.
    Glick SD, Maisonneuve IM, Pearl SM. Evidence for roles of kappa-opioid and NMDA receptors in the mechanism of action of ibogaine.Brain Res. 1997;749:340–343.PubMedCrossRefGoogle Scholar
  117. 117.
    Cappendijk SL, Dzoljic MR. Inhibitory effects of ibogaine on cocaine self-administration in rats.Eur J Pharmacol. 1993;241:261–265.PubMedCrossRefGoogle Scholar
  118. 118.
    Glick SD, Kuehne ME, Raucci J, et al. Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum.Brain Res. 1994;657:14–22.PubMedCrossRefGoogle Scholar
  119. 119.
    Sershen H, Hashim A, Harsing L, Lajtha A. Ibogaine antagonizes cocaine-induced locomotor stimulation in mice.Life Sci. 1992;50:1079–1086.PubMedCrossRefGoogle Scholar
  120. 120.
    Maisonneuve IM Jr, Rossman KL, Jr, Keller RW Jr, Glick SD. Acute and prolonged effects of ibogaine on brain dopamine metabolism and morphine-induced locomotor activity in rats.Brain Res. 1992;575:69–73.PubMedCrossRefGoogle Scholar
  121. 121.
    Szumlinski KK, Maisonneuve IM, Glick SD. Differential effects of ibogaine on behavioural and dopamine sensitization to cocaine.Eur J Pharmacol. 2000;398:259–262.PubMedCrossRefGoogle Scholar
  122. 122.
    Alper KR, Lotsof HS, Frenken GM, Luciano DJ, Bastiaans J. Treatment of acute opioid withdrawal with ibogaine.Am J Addict. 1999;8:234–242.PubMedCrossRefGoogle Scholar
  123. 123.
    O’Hearn E, Molliver ME. The olivocerebellar projection mediates ibogaine-induced degeneration of Purkinje cells: a model of indirect, trans-synaptic excitotoxicity.J Neurosci. 1997;17:8828–8841.PubMedGoogle Scholar
  124. 124.
    Bandarage UK, Kuehne ME, Glick SD. Chemical synthesis and biological evaluation of 18-methoxycoronaridine (18-MC) as a potential anti-addictive agent.Curr Med Chem CNS Agents. 2001;1:113–123.CrossRefGoogle Scholar
  125. 125.
    Kuehne ME, He L, Jokiel PA, et al. Synthesis and biological evaluation of 18-methoxycoronaridine congeners. Potential antiaddiction agents.J Med Chem. 2003;46:2716–2730.PubMedCrossRefGoogle Scholar
  126. 126.
    Glick SD, Maisonneuve IM, Szumlinski KK. 18-Methoxycoronaridine (18-MC) and ibogaine: comparison of antiaddictive efficacy., toxicity, and mechanisms of action.Ann NY Acad Sci. 2000;914:369–386.PubMedCrossRefGoogle Scholar
  127. 127.
    Glick SD, Maisonneuve IM, Dickinson HA. 18-MC reduces methamphetamine and nicotine self-administration in rats.Neuroreport. 2000;11:2013–2015.PubMedCrossRefGoogle Scholar
  128. 128.
    Glick SD, Maisonneuve IM, Szumlinski KK. Mechanisms of action of ibogaine: relevance to putative therapeutic effects and development of a safer iboga alkaloid congener.Alkaloids Chem Biol. 2001;56:39–53.PubMedCrossRefGoogle Scholar
  129. 129.
    Roth BL, Baner K, Westkaemper R, et al. Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist.Proc Natl Acad Sci USA. 2002;99:11934–11939.PubMedCrossRefGoogle Scholar
  130. 130.
    Chavkin C, Sud S, Jin W, et al. Salvinorin A, an active component of the hallucinogenic sageSalvia divinorum is a highly efficacious κ-opioid receptor agonist: structural and functional considerations.J Pharmacol Exp Ther. 2004;308:1197–1203.PubMedCrossRefGoogle Scholar
  131. 131.
    Butelman ER, Harris TJ, Kreek MJ. The plant-derived hallucinogen, salvinorin A, produces kappa-opioid agonist-like discriminative effects in rhesus monkeys.Psychopharmacology (Berl). 2004;172:220–224.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2005

Authors and Affiliations

  • Thomas E. Prisinzano
    • 1
    Email author
  • Kevin Tidgewell
    • 1
  • Wayne W. Harding
    • 1
  1. 1.Division of Medicinal & Natural Products Chemistry, College of PharmacyThe University of IowaIowa City

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