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Discriminative Stimulus Properties of Opioid Ligands: Progress and Future Directions

  • Eduardo R. Butelman
  • Mary Jeanne Kreek
Chapter
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 39)

Abstract

Opioid receptors (MOP-r, KOP-r, DOP-r, as well as NOP-r) and their endogenous neuropeptide agonist systems are involved in diverse neurobiological and behavioral functions, in health and disease. These functions include pain and analgesia, addictions, and psychiatric diseases (e.g., depression-, anxiety-like, and stress-related disorders). Drug discrimination assays have been used to characterize the behavioral pharmacology of ligands with affinity at MOP-r, KOP-r, or DOP-r (and to a lesser extent NOP-r). Therefore, drug discrimination studies with opioid ligands have an important continuing role in translational investigations of diseases that are affected by these neurobiological targets and their pharmacotherapy.

Keywords

Addiction Analgesia Drug discrimination Opioid Prescription opioids 

Notes

Acknowledgements

Experimental work by the authors was supported by the NIH-NIDA grants DA011113 and DA017369 (ERB), and DA05130, which are gratefully acknowledged.

References

  1. 1.
    Colpaert FC (1999) Drug discrimination in neurobiology. Pharmacol Biochem Behav 64:337–345PubMedCrossRefGoogle Scholar
  2. 2.
    Colpaert FC, Niemegeers CJ, Janssen PA (1975) The narcotic cue: evidence for the specificity of the stimulus properties of narcotic drugs. Arch Int Pharmacodyn Ther 218:268–276PubMedGoogle Scholar
  3. 3.
    Colpaert FC, Niemegeers CJ, Janssen PA (1976) The narcotic discriminative stimulus complex: relation to analgesic activity. J Pharm Pharmacol 28:183–187PubMedCrossRefGoogle Scholar
  4. 4.
    Hein DW, Young AM, Herling S, Woods JH (1981) Pharmacological analysis of the discriminative stimulus characteristics of ethylketazocine in the rhesus monkey. J Pharmacol Exp Ther 218:7–15PubMedGoogle Scholar
  5. 5.
    Schaefer GJ, Holtzman SG (1978) Discriminative effects of cyclazocine in the squirrel monkey. J Pharmacol Exp Ther 205:291–301PubMedGoogle Scholar
  6. 6.
    Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE (1976) The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197:517–532PubMedGoogle Scholar
  7. 7.
    Woods JH, Young AM, Herling S (1982) Classification of narcotics on the basis of their reinforcing, discriminative, and antagonist effects in rhesus monkeys. Fed Proc 41:221–227PubMedGoogle Scholar
  8. 8.
    Butelman ER, Ko MC, Traynor JR, Vivian JA, Kreek MJ, Woods JH (2001) GR89,696: a potent kappa-opioid agonist with subtype selectivity in rhesus monkeys. J Pharmacol Exp Ther 298:1049–1059PubMedGoogle Scholar
  9. 9.
    France CP, de Costa BR, Jacobson AE, Rice KC, Woods JH (1990) Apparent affinity of opioid antagonists in morphine-treated rhesus monkeys discriminating between saline and naltrexone. J Pharmacol Exp Ther 252:600–604PubMedGoogle Scholar
  10. 10.
    Brandt MR, Negus SS, Mello NK, Furness MS, Zhang X, Rice KC (1999) Discriminative stimulus effects of the nonpeptidic delta-opioid agonist SNC80 in rhesus monkeys. J Pharmacol Exp Ther 290:1157–1164PubMedGoogle Scholar
  11. 11.
    Carey GJ, Bergman J (2001) Enadoline discrimination in squirrel monkeys: effects of opioid agonists and antagonists. J Pharmacol Exp Ther 297:215–223PubMedGoogle Scholar
  12. 12.
    Dykstra LA, Gmerek DE, Winger G, Woods JH (1987) Kappa opioids in rhesus monkeys. I. Diuresis, sedation, analgesia and discriminative stimulus effects. J Pharmacol Exp Ther 242:413–420PubMedGoogle Scholar
  13. 13.
    Mori T, Yoshizawa K, Ueno T, Nishiwaki M, Shimizu N, Shibasaki M, Narita M, Suzuki T (2013) Involvement of dopamine D2 receptor signal transduction in the discriminative stimulus effects of the kappa-opioid receptor agonist U-50,488H in rats. Behav Pharmacol 24:275–281PubMedCrossRefGoogle Scholar
  14. 14.
    Comer SD, McNutt RW, Chang KJ, De Costa BR, Mosberg HI, Woods JH (1993) Discriminative stimulus effects of BW373U86: a nonpeptide ligand with selectivity for delta opioid receptors. J Pharmacol Exp Ther 267:866–874PubMedGoogle Scholar
  15. 15.
    Dykstra LA, Gmerek DE, Winger G, Woods JH (1987) Kappa opioids in rhesus monkeys. II. Analysis of the antagonistic actions of quadazocine and beta-funaltrexamine. J Pharmacol Exp Ther 242:421–427PubMedGoogle Scholar
  16. 16.
    Walker EA, Young AM (2002) Clocinnamox distinguishes opioid agonists according to relative efficacy in normal and morphine-treated rats trained to discriminate morphine. J Pharmacol Exp Ther 302:101–110PubMedCrossRefGoogle Scholar
  17. 17.
    Harun N, Hassan Z, Navaratnam V, Mansor SM, Shoaib M (2015) Discriminative stimulus properties of mitragynine (kratom) in rats. Psychopharmacology (Berl) 232:2227–2238Google Scholar
  18. 18.
    Strickland JC, Rush CR, Stoops WW (2015) Mu opioid mediated discriminative-stimulus effects of tramadol: an individual subjects analysis. J Exp Anal Behav 103:361–374Google Scholar
  19. 19.
    Comer SD, France CP, Woods JH (1991) Training dose: influences in opioid drug discrimination. NIDA Res Monogr 116:145–161Google Scholar
  20. 20.
    Stolerman IP, Childs E, Ford MM, Grant KA (2011) Role of training dose in drug discrimination: a review. Behav Pharmacol 22:415–429PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Zhang L, Walker EA, Sutherland J 2nd, Young AM (2000) Discriminative stimulus effects of two doses of fentanyl in rats: pharmacological selectivity and effect of training dose on agonist and antagonist effects of mu opioids. Psychopharmacology (Berl) 148:136–145CrossRefGoogle Scholar
  22. 22.
    Bi J (2006) Sensory discrimination tests and measurements: statistical principles, procedures and tables. Blackwell, AmesGoogle Scholar
  23. 23.
    Emmerson PJ, Clark MJ, Mansour A, Akil H, Woods JH, Medzihradsky F (1996) Characterization of opioid agonist efficacy in a C6 glioma cell line expressing the mu opioid receptor. J Pharmacol Exp Ther 278:1121–1127PubMedGoogle Scholar
  24. 24.
    Peckham EM, Traynor JR (2006) Comparison of the antinociceptive response to morphine and morphine-like compounds in male and female Sprague–Dawley rats. J Pharmacol Exp Ther 316:1195–1201PubMedCrossRefGoogle Scholar
  25. 25.
    Traynor JR, Nahorski SR (1995) Modulation by mu-opioid agonists of guanosine-5′-O-(3-[35S]thio)triphosphate binding to membranes from human neuroblastoma SH-SY5Y cells. Mol Pharmacol 47:848–854PubMedGoogle Scholar
  26. 26.
    Bickel WK, Bigelow GE, Preston KL, Liebson IA (1989) Opioid drug discrimination in humans: stability, specificity and relation to self-reported drug effect. J Pharmacol Exp Ther 251:1053–1063PubMedGoogle Scholar
  27. 27.
    Kamien JB, Bickel WK, Hughes JR, Higgins ST, Smith BJ (1993) Drug discrimination by humans compared to nonhumans: current status and future directions. Psychopharmacology (Berl) 111:259–270CrossRefGoogle Scholar
  28. 28.
    Jones HE, Bigelow GE, Preston KL (1999) Assessment of opioid partial agonist activity with a three-choice hydromorphone dose-discrimination procedure. J Pharmacol Exp Ther 289:1350–1361PubMedGoogle Scholar
  29. 29.
    Remmers AE, Clark MJ, Mansour A, Akil H, Woods JH, Medzihradsky F (1999) Opioid efficacy in a C6 glioma cell line stably expressing the human kappa opioid receptor. J Pharmacol Exp Ther 288:827–833PubMedGoogle Scholar
  30. 30.
    Zhu J, Luo LY, Li JG, Chen C, Liu-Chen LY (1997) Activation of the cloned human kappa opioid receptor by agonists enhances [35S]GTPgammaS binding to membranes: determination of potencies and efficacies of ligands. J Pharmacol Exp Ther 282:676–684PubMedGoogle Scholar
  31. 31.
    Preston KL, Bigelow GE (2000) Effects of agonist–antagonist opioids in humans trained in a hydromorphone/not hydromorphone discrimination. J Pharmacol Exp Ther 295:114–124PubMedGoogle Scholar
  32. 32.
    Kreek MJ, Levran O, Reed B, Schlussman SD, Zhou Y, Butelman ER (2012) Opiate addiction and cocaine addiction: underlying molecular neurobiology and genetics. J Clin Invest 122:3387–3393PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Yaksh TL, Wallace MS (2011) Opioids, analgesia and pain management. In: Brunton L, Chabner B, Knollman B (eds) Goodman and Gilman’s the pharmacological basis of therapeutics, 12th edn. McGraw-Hill, New YorkGoogle Scholar
  34. 34.
    C.D.C. (2015) Injury prevention & control: prescription drug overdose. From http://www.cdc.gov/DrugOverdose/
  35. 35.
    Dart RC, Surratt HL, Cicero TJ, Parrino MW, Severtson SG, Bucher-Bartelson B, Green JL (2015) Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med 372:241–248PubMedCrossRefGoogle Scholar
  36. 36.
    Di Chiara G, Imperato A (1988) 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 244:1067–1080PubMedGoogle Scholar
  37. 37.
    Spanagel R, Herz A, Shippenberg TS (1992) Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci U S A 89:2046–2050PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Colpaert FC, Niemegeers CJ (1975) On the narcotic cuing action of fentanyl and other narcotic analgesic drugs. Arch Int Pharmacodyn Ther 217:170–172PubMedGoogle Scholar
  39. 39.
    Jarbe TU (1978) Discriminative effects of morphine in the pigeon. Pharmacol Biochem Behav 9:411–416PubMedCrossRefGoogle Scholar
  40. 40.
    Woods JH, Herling S, Valentino RJ, Hein DW, Coale EH Jr (1979) Narcotic drug discriminations by rhesus monkeys and pigeons. NIDA Res Monogr 27:128–134PubMedGoogle Scholar
  41. 41.
    Platt DM, Rowlett JK, Spealman RD (2001) Discriminative stimulus effects of intravenous heroin and its metabolites in rhesus monkeys: opioid and dopaminergic mechanisms. J Pharmacol Exp Ther 299:760–767PubMedGoogle Scholar
  42. 42.
    Colpaert FC, Niemegeers CJ, Janssen PA (1976) Fentanyl and apomorphine: asymmetrical generalization of discriminative stimulus properties. Neuropharmacology 15:541–545PubMedCrossRefGoogle Scholar
  43. 43.
    Herling S, Woods JH (1981) Discriminative stimulus effects of etorphine in Rhesus monkeys. Psychopharmacology (Berl) 72:265–267CrossRefGoogle Scholar
  44. 44.
    Preston KL, Bigelow GE, Bickel WK, Liebson IA (1989) Drug discrimination in human postaddicts: agonist–antagonist opioids. J Pharmacol Exp Ther 250:184–196PubMedGoogle Scholar
  45. 45.
    Gerak LR, France CP (1996) Discriminative stimulus effects of nalbuphine in rhesus monkeys. J Pharmacol Exp Ther 276:523–531PubMedGoogle Scholar
  46. 46.
    Negus SS, Picker MJ, Dykstra LA (1989) Kappa antagonist effects of buprenorphine in the rat drug-discrimination procedure. NIDA Res Monogr 95:518–519PubMedGoogle Scholar
  47. 47.
    Picker MJ, Craft RM, Negus SS, Powell KR, Mattox SR, Jones SR, Hargrove BK, Dykstra LA (1992) Intermediate efficacy mu opioids: examination of their morphine-like stimulus effects and response rate-decreasing effects in morphine-tolerant rats. J Pharmacol Exp Ther 263:668–681PubMedGoogle Scholar
  48. 48.
    Barrett AC, Smith ES, Picker MJ (2003) Use of irreversible antagonists to determine the relative efficacy of mu-opioids in a pigeon drug discrimination procedure: comparison of beta-funaltrexamine and clocinnamox. J Pharmacol Exp Ther 305:1061–1070PubMedCrossRefGoogle Scholar
  49. 49.
    Burke TF, Woods JH, Lewis JW, Medzihradsky F (1994) Irreversible opioid antagonist effects of clocinnamox on opioid analgesia and mu receptor binding in mice. J Pharmacol Exp Ther 271:715–721PubMedGoogle Scholar
  50. 50.
    Comer SD, Burke TF, Lewis JW, Woods JH (1992) Clocinnamox: a novel, systemically-active, irreversible opioid antagonist. J Pharmacol Exp Ther 262:1051–1056PubMedGoogle Scholar
  51. 51.
    Zernig G, Burke T, Lewis JW, Woods JH (1996) Mechanism of clocinnamox blockade of opioid receptors: evidence from in vitro and ex vivo binding and behavioral assays. J Pharmacol Exp Ther 279:23–31PubMedGoogle Scholar
  52. 52.
    Carter LP, Griffiths RR (2009) Principles of laboratory assessment of drug abuse liability and implications for clinical development. Drug Alcohol Depend 105(Suppl 1):S14–25PubMedCrossRefGoogle Scholar
  53. 53.
    Glennon RA, Young R, Negus SS, Banks ML (2011) Making the right choice: lessons from drug discrimination for research on drug reinforcement and drug self-administration. In: Glennon RA, Young R (eds) Drug discrimination: applications to medicinal chemistry and drug studies. Wiley, New YorkCrossRefGoogle Scholar
  54. 54.
    Marusich JA, Lefever TW, Novak SP, Blough BE, Wiley JL (2013) Prediction and prevention of prescription drug abuse: role of preclinical assessment of substance abuse liability. Methods Rep RTI Press 1–14Google Scholar
  55. 55.
    Negus SS, Fantegrossi W (2008) Overview of conference on preclinical abuse liability testing: current methods and future challenges. Drug Alcohol Depend 92:301–306PubMedCrossRefGoogle Scholar
  56. 56.
    O’Brien CP (2011) Drug addiction. In: Brunton L, Chabner B, Knollman B (eds) Goodman and Gilman’s the pharmacological basis of therapeutics, 12th edn. McGraw-Hill, New YorkGoogle Scholar
  57. 57.
    Williams JT, Ingram SL, Henderson G, Chavkin C, von Zastrow M, Schulz S, Koch T, Evans CJ, Christie MJ (2013) Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 65:223–254PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Colpaert FC, Kuyps JJ, Niemegeers CJ, Janssen PA (1976) Discriminative stimulus properties of fentanyl and morphine: tolerance and dependence. Pharmacol Biochem Behav 5:401–408PubMedCrossRefGoogle Scholar
  59. 59.
    Galici R, McMahon LR, France CP (2005) Cross-tolerance and mu agonist efficacy in pigeons treated with LAAM or buprenorphine. Pharmacol Biochem Behav 81:626–634PubMedCrossRefGoogle Scholar
  60. 60.
    Paronis CA, Holtzman SG (1994) Sensitization and tolerance to the discriminative stimulus effects of mu-opioid agonists. Psychopharmacology (Berl) 114:601–610CrossRefGoogle Scholar
  61. 61.
    Young AM, Kapitsopoulos G, Makhay MM (1991) Tolerance to morphine-like stimulus effects of mu opioid agonists. J Pharmacol Exp Ther 257:795–805PubMedGoogle Scholar
  62. 62.
    Gold MS, Pottash AL, Sweeney DR, Kleber HD (1980) Efficacy of clonidine in opiate withdrawal: a study of thirty patients. Drug Alcohol Depend 6:201–208PubMedCrossRefGoogle Scholar
  63. 63.
    Ignar DM, Kuhn CM (1990) Effects of specific mu and kappa opiate tolerance and abstinence on hypothalamo-pituitary-adrenal axis secretion in the rat. J Pharmacol Exp Ther 255:1287–1295PubMedGoogle Scholar
  64. 64.
    Rosen MI, McMahon TJ, Hameedi FA, Pearsall HR, Woods SW, Kreek MJ, Kosten TR (1996) Effect of clonidine pretreatment on naloxone-precipitated opiate withdrawal. J Pharmacol Exp Ther 276:1128–1135PubMedGoogle Scholar
  65. 65.
    McClung CA, Nestler EJ, Zachariou V (2005) Regulation of gene expression by chronic morphine and morphine withdrawal in the locus ceruleus and ventral tegmental area. J Neurosci 25:6005–6015PubMedCrossRefGoogle Scholar
  66. 66.
    Seip-Cammack KM, Reed B, Zhang Y, Ho A, Kreek MJ (2012) Tolerance and sensitization to chronic escalating dose heroin following extended withdrawal in Fischer rats: possible role of mu-opioid receptors. Psychopharmacology (Berl) 225:127–140Google Scholar
  67. 67.
    Zhou Y, Bendor J, Hofmann L, Randesi M, Ho A, Kreek MJ (2006) Mu opioid receptor and orexin/hypocretin mRNA levels in the lateral hypothalamus and striatum are enhanced by morphine withdrawal. J Endocrinol 191:137–145PubMedCrossRefGoogle Scholar
  68. 68.
    Hutcheson DM, Everitt BJ, Robbins TW, Dickinson A (2001) The role of withdrawal in heroin addiction: enhances reward or promotes avoidance? Nat Neurosci 4:943–947PubMedCrossRefGoogle Scholar
  69. 69.
    Stinus L, Cador M, Zorrilla EP, Koob GF (2005) Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats. Neuropsychopharmacology 30:90–98PubMedCrossRefGoogle Scholar
  70. 70.
    France CP, Woods JH (1989) Discriminative stimulus effects of naltrexone in morphine-treated rhesus monkeys. J Pharmacol Exp Ther 250:937–943PubMedGoogle Scholar
  71. 71.
    Becker GL, Gerak LR, Koek W, France CP (2008) Antagonist-precipitated and discontinuation-induced withdrawal in morphine-dependent rhesus monkeys. Psychopharmacology (Berl) 201:373–382CrossRefGoogle Scholar
  72. 72.
    White DA, Holtzman SG (2003) Discriminative stimulus effects of acute morphine followed by naltrexone in the squirrel monkey. Psychopharmacology (Berl) 167:203–210CrossRefGoogle Scholar
  73. 73.
    Schluger JH, Ho A, Borg L, Porter M, Maniar S, Gunduz M, Perret G, King A, Kreek MJ (1998) Nalmefene causes greater hypothalamic-pituitary-adrenal axis activation than naloxone in normal volunteers: implications for the treatment of alcoholism. Alcohol Clin Exp Res 22:1430–1436PubMedCrossRefGoogle Scholar
  74. 74.
    Williams KL, Ko MC, Rice KC, Woods JH (2003) Effect of opioid receptor antagonists on hypothalamic-pituitary-adrenal activity in rhesus monkeys. Psychoneuroendocrinology 28:513–528PubMedCrossRefGoogle Scholar
  75. 75.
    Katz JL (1986) Effects of clonidine and morphine on opioid withdrawal in rhesus monkeys. Psychopharmacology (Berl) 88:392–397CrossRefGoogle Scholar
  76. 76.
    Oliveto A, Sevarino K, McCance-Katz E, Benios T, Poling J, Feingold A (2003) Clonidine and yohimbine in opioid-dependent humans responding under a naloxone novel-response discrimination procedure. Behav Pharmacol 14:97–109PubMedCrossRefGoogle Scholar
  77. 77.
    Meert TF, Vermeirsch HA (2005) A preclinical comparison between different opioids: antinociceptive versus adverse effects. Pharmacol Biochem Behav 80:309–326PubMedCrossRefGoogle Scholar
  78. 78.
    Walker EA, Makhay MM, House JD, Young AM (1994) In vivo apparent pA2 analysis for naltrexone antagonism of discriminative stimulus and analgesic effects of opiate agonists in rats. J Pharmacol Exp Ther 271:959–968PubMedGoogle Scholar
  79. 79.
    Gauvin DV, McComb M, Code R, Dalton JA, Baird TJ (2015) Abuse liability assessment of hydrocodone under current draft regulatory guidelines. J Pharmacol Toxicol Methods 75:118–129PubMedCrossRefGoogle Scholar
  80. 80.
    Solinas M, Panlilio LV, Justinova Z, Yasar S, Goldberg SR (2006) Using drug-discrimination techniques to study the abuse-related effects of psychoactive drugs in rats. Nat Protoc 1:1194–1206PubMedCrossRefGoogle Scholar
  81. 81.
    Mansour A, Fox CA, Meng F, Akil H, Watson SJ (1994) Kappa 1 receptor mRNA distribution in the rat CNS: comparison to kappa receptor binding and prodynorphin mRNA. Mol Cell Neurosci 5:124–144PubMedCrossRefGoogle Scholar
  82. 82.
    Mathieu-Kia AM, Fan LQ, Kreek MJ, Simon EJ, Hiller JM (2001) Mu-, delta- and kappa-opioid receptor populations are differentially altered in distinct areas of postmortem brains of Alzheimer’s disease patients. Brain Res 893:121–134PubMedCrossRefGoogle Scholar
  83. 83.
    Simonin F, Gaveriaux-Ruff C, Befort K, Matthes H, Lannes B, Micheletti G, Mattei MG, Charron G, Bloch B, Kieffer B (1995) kappa-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc Natl Acad Sci U S A 92:7006–7010PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Johnson MW, MacLean KA, Reissig CJ, Prisinzano TE, Griffiths RR (2011) Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum. Drug Alcohol Depend 115:150–155PubMedCrossRefGoogle Scholar
  85. 85.
    Pfeiffer A, Brantl V, Herz A, Emrich HM (1986) Psychotomimesis mediated by kappa opiate receptors. Science 233:774–776PubMedCrossRefGoogle Scholar
  86. 86.
    Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ (2005) 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. Psychopharmacology (Berl) 179:551–558CrossRefGoogle Scholar
  87. 87.
    Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ (2004) Effect of the endogenous kappa opioid agonist dynorphin A(1–17) on cocaine-evoked increases in striatal dopamine levels and cocaine-induced place preference in C57BL/6J mice. Psychopharmacology (Berl) 172:422–429CrossRefGoogle Scholar
  88. 88.
    Beardsley PM, Howard JL, Shelton KL, Carroll FI (2005) Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats. Psychopharmacology (Berl) 183:118–126CrossRefGoogle Scholar
  89. 89.
    Butelman ER, Yuferov V, Kreek MJ (2012) kappa-opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction. Trends Neurosci 35:587–596PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Schlosburg JE, Whitfield TW Jr, Park PE, Crawford EF, George O, Vendruscolo LF, Koob GF (2013) Long-term antagonism of kappa opioid receptors prevents escalation of and increased motivation for heroin intake. J Neurosci 33:19384–19392PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Wang XM, Zhou Y, Spangler R, Ho A, Han JS, Kreek MJ (1999) Acute intermittent morphine increases preprodynorphin and kappa opioid receptor mRNA levels in the rat brain. Brain Res Mol Brain Res 66:184–187PubMedCrossRefGoogle Scholar
  92. 92.
    Zhou Y, Leri F, Grella S, Aldrich J, Kreek MJ (2013) Involvement of dynorphin and kappa opioid receptor in yohimbine-induced reinstatement of heroin seeking in rats. Synapse 67:358–361PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Chang C, Byon W, Lu Y, Jacobsen LK, Badura LL, Sawant-Basak A, Miller E, Liu J, Grimwood S, Wang EQ, Maurer TS (2011) Quantitative PK-PD model-based translational pharmacology of a novel kappa opioid receptor antagonist between rats and humans. AAPS J 13:565–575Google Scholar
  94. 94.
    Kreek MJ, Schluger J, Borg L, Gunduz M, Ho A (1999) Dynorphin A1-13 causes elevation of serum levels of prolactin through an opioid receptor mechanism in humans: gender differences and implications for modulation of dopaminergic tone in the treatment of addictions. J Pharmacol Exp Ther 288:260–269PubMedGoogle Scholar
  95. 95.
    Lowe SL, Wong CJ, Witcher J, Gonzales CR, Dickinson GL, Bell RL, Rorick-Kehn L, Weller M, Stoltz RR, Royalty J, Tauscher-Wisniewski S (2014) Safety, tolerability, and pharmacokinetic evaluation of single- and multiple-ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects. J Clin Pharmacol 54:968–978PubMedCrossRefGoogle Scholar
  96. 96.
    Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB (2002) Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proc Natl Acad Sci U S A 99:11934–11939PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Baker LE, Panos JJ, Killinger BA, Peet MM, Bell LM, Haliw LA, Walker SL (2009) Comparison of the discriminative stimulus effects of salvinorin A and its derivatives to U69,593 and U50,488 in rats. Psychopharmacology (Berl) 203:203–211CrossRefGoogle Scholar
  98. 98.
    Butelman ER, Rus S, Prisinzano TE, Kreek MJ (2010) The discriminative effects of the kappa-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects. Psychopharmacology (Berl) 210:253–262CrossRefGoogle Scholar
  99. 99.
    Li JX, Rice KC, France CP (2008) Discriminative stimulus effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane in rhesus monkeys. J Pharmacol Exp Ther 324:827–833PubMedCrossRefGoogle Scholar
  100. 100.
    Addy PH (2012) Acute and post-acute behavioral and psychological effects of salvinorin A in humans. Psychopharmacology (Berl) 220:195–204CrossRefGoogle Scholar
  101. 101.
    Maqueda AE, Valle M, Addy PH, Antonijoan RM, Puntes M, Coimbra J, Ballester MR, Garrido M, Gonzalez M, Claramunt J, Barker S, Johnson MW, Griffiths RR, Riba J (2015) Salvinorin-A induces intense dissociative effects, blocking external sensory perception and modulating interoception and sense of body ownership in humans. Int J Neuropsychopharmacol 18:1–14Google Scholar
  102. 102.
    Mori T, Yoshizawa K, Shibasaki M, Suzuki T (2012) Discriminative stimulus effects of hallucinogenic drugs: a possible relation to reinforcing and aversive effects. J Pharmacol Sci 120:70–76PubMedCrossRefGoogle Scholar
  103. 103.
    Krueger RF, Hopwood CJ, Wright AG, Markon KE (2014) Challenges and strategies in helping the DSM become more dimensional and empirically based. Curr Psychiatry Rep 16:515–521PubMedCrossRefGoogle Scholar
  104. 104.
    NIMH-NIH (2011) NIMH research domain criteria (RDoC), 2013. From http://www.nimh.nih.gov/research-priorities/rdoc/nimh-research-domain-criteria-rdoc.shtml
  105. 105.
    Butelman ER, Ball JW, Kreek MJ (2002) Comparison of the discriminative and neuroendocrine effects of centrally penetrating kappa-opioid agonists in rhesus monkeys. Psychopharmacology (Berl) 164:115–120CrossRefGoogle Scholar
  106. 106.
    Jewett DC, Mosberg HI, Woods JH (1996) Discriminative stimulus effects of a centrally administered, delta-opioid peptide (D-Pen2-D-Pen5-enkephalin) in pigeons. Psychopharmacology (Berl) 127:225–230CrossRefGoogle Scholar
  107. 107.
    Peluso J, LaForge KS, Matthes HW, Kreek MJ, Kieffer BL, Gaveriaux-Ruff C (1998) Distribution of nociceptin/orphanin FQ receptor transcript in human central nervous system and immune cells. J Neuroimmunol 81:184–192PubMedCrossRefGoogle Scholar
  108. 108.
    Cami-Kobeci G, Polgar W, Khroyan TV, Toll LR, Husbands SM (2011) Structural determinants of opioid and NOP receptor activity in derivatives of buprenorphine. J Med ChemGoogle Scholar
  109. 109.
    Chiou LC, Liao YY, Fan PC, Kuo PH, Wang CH, Riemer C, Prinssen EP (2007) Nociceptin/orphanin FQ peptide receptors: pharmacology and clinical implications. Curr Drug Targets 8:117–135PubMedCrossRefGoogle Scholar
  110. 110.
    Ding H, Hayashida K, Suto T, Sukhtankar DD, Kimura M, Mendenhall V, Ko MC (2015) Supraspinal actions of nociceptin/orphanin FQ, morphine and substance P in regulating pain and itch in non-human primates. Br J Pharmacol 172:3302–3312PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Ko MC, Woods JH, Fantegrossi WE, Galuska CM, Wichmann J, Prinssen EP (2009) Behavioral effects of a synthetic agonist selective for nociceptin/orphanin FQ peptide receptors in monkeys. Neuropsychopharmacology 34:2088–2096PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Recker MD, Higgins GA (2004) The opioid receptor like-1 receptor agonist Ro 64-6198 (1S,3aS-8-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one) produces a discriminative stimulus in rats distinct from that of a mu, kappa, and delta opioid receptor agonist cue. J Pharmacol Exp Ther 311:652–658PubMedCrossRefGoogle Scholar
  113. 113.
    Saccone PA, Zelenock KA, Lindsey A, Zaks ME, Woods JH (2015) Characterization of the discriminative stimulus effects of the NOP agonist Ro 64-6198 in non-human primates. Drug Alcohol Depend 146, e86CrossRefGoogle Scholar
  114. 114.
    Luttrell LM, Maudsley S, Bohn LM (2015) Fulfilling the promise of ‘biased’ GPCR agonism. Mol Pharmacol 88:579–588Google Scholar
  115. 115.
    White KL, Scopton AP, Rives ML, Bikbulatov RV, Polepally PR, Brown PJ, Kenakin T, Javitch JA, Zjawiony JK, Roth BL (2014) Identification of novel functionally selective kappa-opioid receptor scaffolds. Mol Pharmacol 85:83–90PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Krivsky JA, Stoffel EC, Sumner JE, Inman BC, Craft RM (2006) Role of ventral tegmental area, periaqueductal gray and parabrachial nucleus in the discriminative stimulus effects of morphine in the rat. Behav Pharmacol 17:259–270PubMedCrossRefGoogle Scholar
  117. 117.
    Shoaib M, Spanagel R (1994) Mesolimbic sites mediate the discriminative stimulus effects of morphine. Eur J Pharmacol 252:69–75PubMedCrossRefGoogle Scholar
  118. 118.
    Yoshizawa K, Narita M, Saeki M, Isotani K, Horiuchi H, Imai S, Kuzumaki N, Suzuki T (2011) Activation of extracellular signal-regulated kinase is critical for the discriminative stimulus effects induced by U-50,488H. Synapse 65:1052–1061PubMedCrossRefGoogle Scholar
  119. 119.
    Cuthbert BN (2014) Translating intermediate phenotypes to psychopathology: the NIMH Research Domain Criteria. Psychophysiology 51:1205–1206PubMedCrossRefGoogle Scholar
  120. 120.
    Craft RM (2008) Sex differences in analgesic, reinforcing, discriminative, and motoric effects of opioids. Exp Clin Psychopharmacol 16:376–385PubMedCrossRefGoogle Scholar
  121. 121.
    Neelakantan H, Ward SJ, Walker EA (2015) Discriminative stimulus effects of morphine and oxycodone in the absence and presence of acetic acid in male and female C57Bl/6 mice. Exp Clin Psychopharmacol 23:217–227PubMedCrossRefGoogle Scholar
  122. 122.
    Craft RM, Kruzich PJ, Boyer JS, Harding JW, Hanesworth JM (1998) Sex differences in discriminative stimulus and diuretic effects of the kappa opioid agonist U69,593 in the rat. Pharmacol Biochem Behav 61:395–403PubMedCrossRefGoogle Scholar
  123. 123.
    Clayton JA, Collins FS (2014) Policy: NIH to balance sex in cell and animal studies. Nature 509:282–283PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Back SE, Payne RA, Waldrop AE, Smith A, Reeves S, Brady KT (2009) Prescription opioid aberrant behaviors: a pilot study of sex differences. Clin J Pain 25:477–484PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Kuhn C (2015) Emergence of sex differences in the development of substance use and abuse during adolescence. Pharmacol Ther 153:55–78Google Scholar
  126. 126.
    Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L, Gong J, Schluger J, Strong JA, Leal SM, Tischfield JA, Kreek MJ, Yu L (1998) Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A 95:9608–9613PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Morgan D, Cook CD, Picker MJ (1999) Sensitivity to the discriminative stimulus and antinociceptive effects of mu opioids: role of strain of rat, stimulus intensity, and intrinsic efficacy at the mu opioid receptor. J Pharmacol Exp Ther 289:965–975PubMedGoogle Scholar
  128. 128.
    Nielsen DA, Yuferov V, Hamon S, Jackson C, Ho A, Ott J, Kreek MJ (2009) Increased OPRM1 DNA methylation in lymphocytes of methadone-maintained former heroin addicts. Neuropsychopharmacology 34:867–873PubMedCrossRefGoogle Scholar
  129. 129.
    Picetti R, Caccavo JA, Ho A, Kreek MJ (2012) Dose escalation and dose preference in extended-access heroin self-administration in Lewis and Fischer rats. Psychopharmacology (Berl) 220:163–172CrossRefGoogle Scholar
  130. 130.
    Reed B, Butelman ER, Yuferov V, Randesi M, Kreek MJ (2014) Genetics of opiate addiction. Curr Psychiatry Rep 16:504PubMedCrossRefGoogle Scholar
  131. 131.
    Bruchas MR, Land BB, Chavkin C (2010) The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res 1314:44–55PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Laboratory on the Biology of Addictive DiseasesThe Rockefeller UniversityNew YorkUSA

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