Abstract
Background
Initial hypotheses regarding the role of the κ opioid system in drug addiction suggested that κ receptor stimulation had anti-addictive effects. However, recent research suggests that κ receptor antagonists may reverse motivational aspects of dependence. In the present review, we revisit the studies that measured the effects of κ receptor ligands on the reinforcing and rewarding effects of drugs and postulate underlying neurobiological mechanisms for these effects to elaborate a more complex view of the role of κ receptor ligands in drug addiction.
Results
The review of studies indicates that κ receptor stimulation generally antagonizes the acute reinforcing/rewarding effects of drugs whereas κ receptor blockade has no consistent effect. However, in a drug dependent-like state, κ receptor blockade was effective in reducing increased drug intake. In animal models of reinstatement, κ receptor stimulation can induce reinstatement via a stress-like mechanism. Results in conditioned place preference/aversion and intracranial self-stimulation indicate that κ receptor agonists produce, respectively, aversive-like and dysphoric-like effects. Additionally, preclinical and postmortem studies show that administration or self-administration of cocaine, ethanol, and heroin activate the κ opioid system.
Conclusion
κ receptor agonists antagonize the reinforcing/rewarding effects of drugs possibly through punishing/aversive-like effects and reinstate drug seeking through stress-like effects. Evidence suggests that abused drugs activate the κ opioid system, which may play a key role in motivational aspects of dependence. Kappa opioid systems may have an important role in driving compulsive drug intake.
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Abbreviations
- Positive reinforcement:
-
defined as the process by which presentation of a stimulus (drug) increases the probability of a response (nondependent drug-taking paradigms)
- Punishment:
-
defined as the process by which presentation of a stimulus (drug) decreases the probability of a response (nondependent drug-taking paradigms)
- Negative reinforcement:
-
defined as a process by which removal of an aversive stimulus (negative emotional state of drug withdrawal) increases the probability of a response (dependence-induced drug taking)
- Reward:
-
defined as a stimulus (drug) that increases the probability of a response, but usually includes a positive hedonic connotation
- Stress:
-
anything that causes an alteration in psychological homeostatic processes
- Neuroadaptation:
-
changes in function of a given neuronal system to a drug
- Noxious (aversive) stimulus:
-
stimuli that arouse emotional reactions of distress, and the termination of them induces relief
References
Acri JB, Thompson AC, Shippenberg T (2001) Modulation of pre- and postsynaptic dopamine D2 receptor function by the selective kappa-opioid receptor agonist U69593. Synapse 39:343–350
Anderson SM, Bari AA, Pierce RC (2003) Administration of the D1-like dopamine receptor antagonist SCH-23390 into the medial nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug-seeking behavior in rats. Psychopharmacology (Berl) 168:132–138
Anderson SM, Schmidt HD, Pierce RC (2006) Administration of the D2 dopamine receptor antagonist sulpiride into the shell, but not the core, of the nucleus accumbens attenuates cocaine priming-induced reinstatement of drug seeking. Neuropsychopharmacology 31:1452–1461
Badiani A, Stewart J (1992) The kappa-opioid U-50, 488H suppresses the initiation of nocturnal spontaneous drinking in normally hydrated rats. Psychopharmacology (Berl) 106:463–473
Bals-Kubik R, Ableitner A, Herz A, Shippenberg TS (1993) Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats. J Pharmacol Exp Ther 264:489–495
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) 183:118–126
Beczkowska IW, Koch JE, Bostock ME, Leibowitz SF, Bodnar RJ (1993) Central opioid receptor subtype antagonists differentially reduce intake of saccharin and maltose dextrin solutions in rats. Brain Res 618:261–270
Benton D (1985) Mu and kappa opiate receptor involvement in agonistic behaviour in mice. Pharmacol Biochem Behav 23:871–876
Benton D, Smoothy R, Brain PF (1985) Comparisons of the influence of morphine sulphate, morphine-3-glucuronide and tifluadom on social encounters in mice. Physiol Behav 35:689–693
Braida D, Limonta V, Pegorini S, Zani A, Guerini-Rocco C, Gori E, Sala M (2007) Hallucinatory and rewarding effect of salvinorin A in zebrafish: kappa-opioid and CB1-cannabinoid receptor involvement. Psychopharmacology (Berl) 190:441–448
Braida D, Limonta V, Capurro V, Fadda P, Rubino T, Mascia P, Zani A, Gori E, Fratta W, Parolaro D, Sala M (2008) Involvement of kappa-opioid and endocannabinoid system on Salvinorin A-induced reward. Biol Psychiatry 63:286–292
Bruchas MR, Land BB, Chavkin C (2009) The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res
Butelman ER, Negus SS, Ai Y, de Costa BR, Woods JH (1993) Kappa opioid antagonist effects of systemically administered nor-binaltorphimine in a thermal antinociception assay in rhesus monkeys. J Pharmacol Exp Ther 267:1269–1276
Calogero AE, Scaccianoce S, Burrello N, Nicolai R, Muscolo LA, Kling MA, Angelucci L, D’Agata R (1996) The kappa-opioid receptor agonist MR-2034 stimulates the rat hypothalamic-pituitary-adrenal axis: studies in vivo and in vitro. J Neuroendocrinol 8:579–585
Carey AN, Borozny K, Aldrich JV, McLaughlin JP (2007) Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn. Eur J Pharmacol 569:84–89
Carey AN, Lyons AM, Shay CF, Dunton O, McLaughlin JP (2009) Endogenous kappa opioid activation mediates stress-induced deficits in learning and memory. J Neurosci 29:4293–4300
Carlezon WA Jr, Thome J, Olson VG, Lane-Ladd SB, Brodkin ES, Hiroi N, Duman RS, Neve RL, Nestler EJ (1998) Regulation of cocaine reward by CREB. Science 282:2272–2275
Carlezon WA Jr, Beguin C, DiNieri JA, Baumann MH, Richards MR, Todtenkopf MS, Rothman RB, Ma Z, Lee DY, Cohen BM (2006) Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats. J Pharmacol Exp Ther 316:440–447
Carr GV, Bangasser DA, Bethea T, Young M, Valentino RJ, Lucki I (2009) Antidepressant-like effects of kappa-opioid receptor antagonists in Wistar Kyoto rats. Neuropsychopharmacology
Chartoff EH, Papadopoulou M, MacDonald ML, Parsegian A, Potter D, Konradi C, Carlezon WA Jr (2009) Desipramine reduces stress-activated dynorphin expression and CREB phosphorylation in NAc tissue. Mol Pharmacol 75:704–712
Chavkin C, James IF, Goldstein A (1982) Dynorphin is a specific endogenous ligand of the kappa opioid receptor. Science 215:413–415
Chefer VI, Czyzyk T, Bolan EA, Moron J, Pintar JE, Shippenberg TS (2005) Endogenous kappa-opioid receptor systems regulate mesoaccumbal dopamine dynamics and vulnerability to cocaine. J Neurosci 25:5029–5037
Chen X, McClatchy DB, Geller EB, Tallarida RJ, Adler MW (2005) The dynamic relationship between mu and kappa opioid receptors in body temperature regulation. Life Sci 78:329–333
Clarke S, Zimmer A, Zimmer AM, Hill RG, Kitchen I (2003) Region selective up-regulation of micro-, delta- and kappa-opioid receptors but not opioid receptor-like 1 receptors in the brains of enkephalin and dynorphin knockout mice. Neuroscience 122:479–489
Clarke TK, Krause K, Li T, Schumann G (2009) An association of prodynorphin polymorphisms and opioid dependence in females in a Chinese population. Addict Biol 14:366–370
Cooper SJ, Jackson A, Kirkham TC (1985) Endorphins and food intake: kappa opioid receptor agonists and hyperphagia. Pharmacol Biochem Behav 23:889–901
Cosgrove KP, Carroll ME (2002) 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 301:993–1002
Covington HE 3rd, Miczek KA (2001) Repeated social-defeat stress, cocaine or morphine. Effects on behavioral sensitization and intravenous cocaine self-administration “binges”. Psychopharmacology (Berl) 158:388–398
Covington HE 3rd, Kikusui T, Goodhue J, Nikulina EM, Hammer RP Jr, Miczek KA (2005) Brief social defeat stress: long lasting effects on cocaine taking during a binge and zif268 mRNA expression in the amygdala and prefrontal cortex. Neuropsychopharmacology 30:310–321
Crawford CA, McDougall SA, Bolanos CA, Hall S, Berger SP (1995) The effects of the kappa agonist U-50, 488 on cocaine-induced conditioned and unconditioned behaviors and Fos immunoreactivity. Psychopharmacology (Berl) 120:392–399
Crombag HS, Grimm JW, Shaham Y (2002) Effect of dopamine receptor antagonists on renewal of cocaine seeking by reexposure to drug-associated contextual cues. Neuropsychopharmacology 27:1006–1015
Daunais JB, Roberts DC, McGinty JF (1993) Cocaine self-administration increases preprodynorphin, but not c-fos, mRNA in rat striatum. Neuroreport 4:543–546
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 244:1067–1080
Dinieri JA, Nemeth CL, Parsegian A, Carle T, Gurevich VV, Gurevich E, Neve RL, Nestler EJ, Carlezon WA Jr (2009) Altered sensitivity to rewarding and aversive drugs in mice with inducible disruption of cAMP response element-binding protein function within the nucleus accumbens. J Neurosci 29:1855–1859
Doyon WM, Howard EC, Shippenberg TS, Gonzales RA (2006) Kappa-opioid receptor modulation of accumbal dopamine concentration during operant ethanol self-administration. Neuropharmacology 51:487–496
Fagergren P, Smith HR, Daunais JB, Nader MA, Porrino LJ, Hurd YL (2003) Temporal upregulation of prodynorphin mRNA in the primate striatum after cocaine self-administration. Eur J Neurosci 17:2212–2218
Fallon JH, Leslie FM (1986) Distribution of dynorphin and enkephalin peptides in the rat brain. J Comp Neurol 249:293–336
Frankel PS, Alburges ME, Bush L, Hanson GR, Kish SJ (2008) Striatal and ventral pallidum dynorphin concentrations are markedly increased in human chronic cocaine users. Neuropharmacology 55:41–46
Fuentealba JA, Gysling K, Magendzo K, Andres ME (2006) Repeated administration of the selective kappa-opioid receptor agonist U-69593 increases stimulated dopamine extracellular levels in the rat nucleus accumbens. J Neurosci Res 84:450–459
Fuentealba JA, Gysling K, Andres ME (2007) Increased locomotor response to amphetamine induced by the repeated administration of the selective kappa-opioid receptor agonist U-69593. Synapse 61:771–777
Galeote L, Berrendero F, Bura SA, Zimmer A, Maldonado R (2009) Prodynorphin gene disruption increases the sensitivity to nicotine self-administration in mice. Int J Neuropsychopharmacol 12:615–625
Gehrke BJ, Chefer VI, Shippenberg TS (2008) Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum. Psychopharmacology (Berl) 197:509–517
Gerra G, Fantoma A, Zaimovic A (2006) Naltrexone and buprenorphine combination in the treatment of opioid dependence. J Psychopharmacol 20:806–814
Gerra G, Leonardi C, Cortese E, D’Amore A, Lucchini A, Strepparola G, Serio G, Farina G, Magnelli F, Zaimovic A, Mancini A, Turci M, Manfredini M, Donnini C (2007) Human kappa opioid receptor gene (OPRK1) polymorphism is associated with opiate addiction. Am J Med Genet B Neuropsychiatr Genet 144B:771–775
Ghozland S, Matthes HW, Simonin F, Filliol D, Kieffer BL, Maldonado R (2002) Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors. J Neurosci 22:1146–1154
Gilpin NW, Richardson HN, Cole M, Koob GF (2008) Vapor inhalation of alcohol in rats. Curr Protoc Neurosci Chapter 9: Unit 9 29
Glick SD, Maisonneuve IM, Raucci J, Archer S (1995) Kappa opioid inhibition of morphine and cocaine self-administration in rats. Brain Res 681:147–152
Gosnell BA, Grace M, Levine AS (1987) Effects of beta-chlornaltrexamine on food intake, body weight and opioid-induced feeding. Life Sci 40:1459–1467
Handler CM, Geller EB, Adler MW (1992) Effect of mu-, kappa-, and delta-selective opioid agonists on thermoregulation in the rat. Pharmacol Biochem Behav 43:1209–1216
Hartig U, Opitz K (1983) The influence of the kappa-agonist bremazocine on ingestive behaviour in mice and rats. Arch Int Pharmacodyn Ther 262:4–12
Heidbreder CA, Schenk S, Partridge B, Shippenberg TS (1998) Increased responsiveness of mesolimbic and mesostriatal dopamine neurons to cocaine following repeated administration of a selective kappa-opioid receptor agonist. Synapse 30:255–262
Heijna MH, Padt M, Hogenboom F, Portoghese PS, Mulder AH, Schoffelmeer AN (1990) Opioid receptor-mediated inhibition of dopamine and acetylcholine release from slices of rat nucleus accumbens, olfactory tubercle and frontal cortex. Eur J Pharmacol 181:267–278
Hjelmstad GO, Fields HL (2001) Kappa opioid receptor inhibition of glutamatergic transmission in the nucleus accumbens shell. J Neurophysiol 85:1153–1158
Hjelmstad GO, Fields HL (2003) Kappa opioid receptor activation in the nucleus accumbens inhibits glutamate and GABA release through different mechanisms. J Neurophysiol 89:2389–2395
Holter SM, Henniger MS, Lipkowski AW, Spanagel R (2000) Kappa-opioid receptors and relapse-like drinking in long-term ethanol-experienced rats. Psychopharmacology (Berl) 153:93–102
Horan P, Taylor J, Yamamura HI, Porreca F (1992) Extremely long-lasting antagonistic actions of nor-binaltorphimine (nor-BNI) in the mouse tail-flick test. J Pharmacol Exp Ther 260:1237–1243
Hurd YL, Herkenham M (1993) Molecular alterations in the neostriatum of human cocaine addicts. Synapse 13:357–369
Hurd YL, Brown EE, Finlay JM, Fibiger HC, Gerfen CR (1992) Cocaine self-administration differentially alters mRNA expression of striatal peptides. Brain Res Mol Brain Res 13:165–170
Ise Y, Narita M, Nagase H, Suzuki T (2002) Modulation of kappa-opioidergic systems on mecamylamine-precipitated nicotine-withdrawal aversion in rats. Neurosci Lett 323:164–166
Iwamoto ET (1981) Locomotor activity and antinociception after putative mu, kappa and sigma opioid receptor agonists in the rat: influence of dopaminergic agonists and antagonists. J Pharmacol Exp Ther 217:451–460
Izenwasser S, Acri JB, Kunko PM, Shippenberg T (1998) Repeated treatment with the selective kappa opioid agonist U-69593 produces a marked depletion of dopamine D2 receptors. Synapse 30:275–283
Jackson A, Cooper SJ (1985) Effects of kappa opiate agonists on palatable food consumption in non-deprived rats, with and without food preloads. Brain Res Bull 15:391–396
Ji D, Gilpin NW, Richardson HN, Rivier CL, Koob GF (2008) Effects of naltrexone, duloxetine, and a corticotropin-releasing factor type 1 receptor antagonist on binge-like alcohol drinking in rats. Behav Pharmacol 19:1–12
Jones DN, Holtzman SG (1992) Long term kappa-opioid receptor blockade following nor-binaltorphimine. Eur J Pharmacol 215:345–348
Khazan N, Young GA, Calligaro D (1983) Self-administration of dynorphin-[1–13] and d-ala2-dynorphin-[1-11] (kappa opioid agonists) in morphine (mu opioid agonist)-dependent rats. Life Sci 33(Suppl 1):559–562
Knoll AT, Carlezon WA Jr (2009) Dynorphin, stress, and depression. Brain Res
Knoll AT, Meloni EG, Thomas JB, Carroll FI, Carlezon WA Jr (2007) Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats. J Pharmacol Exp Ther 323:838–845
Ko MC, Butelman ER, Traynor JR, Woods JH (1998) Differentiation of kappa opioid agonist-induced antinociception by naltrexone apparent pA2 analysis in rhesus monkeys. J Pharmacol Exp Ther 285:518–526
Koob GF (1999a) Corticotropin-releasing factor, norepinephrine, and stress. Biol Psychiatry 46:1167–1180
Koob GF (1999b) Stress, corticotropin-releasing factor, and drug addiction. Ann N Y Acad Sci 897:27–45
Koob GF (2008) A role for brain stress systems in addiction. Neuron 59:11–34
Koob GF (2009) Brain stress systems in the amygdala and addiction. Brain Res 1293:61–75
Koob GF, Le Moal M (2008) Review. Neurobiological mechanisms for opponent motivational processes in addiction. Philos Trans R Soc Lond B Biol Sci 363:3113–3123
Koob GF, Vaccarino FJ, Amalric M, Bloom FE (1986) Neurochemical substrates for opiate reinforcement. NIDA Res Monogr 71:146–164
Koob GF, Heinrichs SC, Pich EM, Menzaghi F, Baldwin H, Miczek K, Britton KT (1993) The role of corticotropin-releasing factor in behavioural responses to stress. Ciba Found Symp 172:277–289, discussion 290–5
Kuzmin AV, Semenova S, Gerrits MA, Zvartau EE, Van Ree JM (1997) Kappa-opioid receptor agonist U50, 488H modulates cocaine and morphine self-administration in drug-naive rats and mice. Eur J Pharmacol 321:265–271
Kuzmin AV, Gerrits MA, Van Ree JM (1998) Kappa-opioid receptor blockade with nor-binaltorphimine modulates cocaine self-administration in drug-naive rats. Eur J Pharmacol 358:197–202
Lahti RA, VonVoigtlander PF, Barsuhn C (1982) Properties of a selective kappa agonist, U-50, 488H. Life Sci 31:2257–2260
Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C (2008) The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. J Neurosci 28:407–414
Land BB, Bruchas MR, Schattauer S, Giardino WJ, Aita M, Messinger D, Hnasko TS, Palmiter RD, Chavkin C (2009) Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking. Proc Natl Acad Sci U S A 106:19168–19173
Leander JD (1983) A kappa opioid effect: increased urination in the rat. J Pharmacol Exp Ther 224:89–94
Lee MD, Clifton PG (1992) Free-feeding and free-drinking patterns of male rats following treatment with opiate kappa agonists. Physiol Behav 52:1179–1185
Lee PH, Obie J, Hong JS (1989) Opioids induce convulsions and wet dog shakes in rats: mediation by hippocampal mu, but not delta or kappa opioid receptors. J Neurosci 9:692–697
Lindholm S, Ploj K, Franck J, Nylander I (2000) Repeated ethanol administration induces short- and long-term changes in enkephalin and dynorphin tissue concentrations in rat brain. Alcohol 22:165–171
Lindholm S, Werme M, Brene S, Franck J (2001) The selective kappa-opioid receptor agonist U50, 488H attenuates voluntary ethanol intake in the rat. Behav Brain Res 120:137–146
Locke KW, Brown DR, Holtzman SG (1982) Effects of opiate antagonists and putative mu- and kappa-agonists on milk intake in rat and squirrel monkey. Pharmacol Biochem Behav 17:1275–1279
Logrip ML, Janak PH, Ron D (2008) Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake. FASEB J 22:2393–2404
Logrip ML, Janak PH, Ron D (2009) Blockade of ethanol reward by the kappa opioid receptor agonist U50, 488H. Alcohol 43:359–365
Lynch WC, Watt J, Krall S, Paden CM (1985) Autoradiographic localization of kappa opiate receptors in CNS taste and feeding areas. Pharmacol Biochem Behav 22:699–705
Mague SD, Pliakas AM, Todtenkopf MS, Tomasiewicz HC, Zhang Y, Stevens WC Jr, Jones RM, Portoghese PS, Carlezon WA Jr (2003) Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats. J Pharmacol Exp Ther 305:323–330
Maisonneuve IM, Archer S, Glick SD (1994) U50, 488, a kappa opioid receptor agonist, attenuates cocaine-induced increases in extracellular dopamine in the nucleus accumbens of rats. Neurosci Lett 181:57–60
Marchant NJ, Densmore VS, Osborne PB (2007) Coexpression of prodynorphin and corticotrophin-releasing hormone in the rat central amygdala: evidence of two distinct endogenous opioid systems in the lateral division. J Comp Neurol 504:702–715
Margolis EB, Hjelmstad GO, Bonci A, Fields HL (2003) Kappa-opioid agonists directly inhibit midbrain dopaminergic neurons. J Neurosci 23:9981–9986
Margolis EB, Lock H, Chefer VI, Shippenberg TS, Hjelmstad GO, Fields HL (2006) Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex. Proc Natl Acad Sci U S A 103:2938–2942
Matsuzawa S, Suzuki T, Misawa M, Nagase H (1998) Involvement of mu- and delta-opioid receptors in the ethanol-associated place preference in rats exposed to foot shock stress. Brain Res 803:169–177
Matsuzawa S, Suzuki T, Misawa M, Nagase H (1999) Different roles of mu-, delta- and kappa-opioid receptors in ethanol-associated place preference in rats exposed to conditioned fear stress. Eur J Pharmacol 368:9–16
McLaughlin JP, Marton-Popovici M, Chavkin C (2003) Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses. J Neurosci 23:5674–5683
McLaughlin JP, Land BB, Li S, Pintar JE, Chavkin C (2006a) Prior activation of kappa opioid receptors by U50, 488 mimics repeated forced swim stress to potentiate cocaine place preference conditioning. Neuropsychopharmacology 31:787–794
McLaughlin JP, Li S, Valdez J, Chavkin TA, Chavkin C (2006b) Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system. Neuropsychopharmacology 31:1241–1248
Mello NK, Negus SS (1998) Effects of kappa opioid agonists on cocaine- and food-maintained responding by rhesus monkeys. J Pharmacol Exp Ther 286:812–824
Mendizabal V, Zimmer A, Maldonado R (2006) Involvement of kappa/dynorphin system in WIN 55, 212–2 self-administration in mice. Neuropsychopharmacology 31:1957–1966
Mitchell JM, Liang MT, Fields HL (2005) A single injection of the kappa opioid antagonist norbinaltorphimine increases ethanol consumption in rats. Psychopharmacology (Berl) 182:384–392
Morani AS, Kivell B, Prisinzano TE, Schenk S (2009) Effect of kappa-opioid receptor agonists U69593, U50488H, spiradoline and salvinorin A on cocaine-induced drug-seeking in rats. Pharmacol Biochem Behav 94:244–249
Mori T, Nomura M, Nagase H, Narita M, Suzuki T (2002) Effects of a newly synthesized kappa-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats. Psychopharmacology (Berl) 161:17–22
Morley JE, Levine AS, Kneip J, Grace M, Zeugner H, Shearman GT (1985) The kappa opioid receptor and food intake. Eur J Pharmacol 112:17–25
Mucha RF, Herz A (1985) Motivational properties of kappa and mu opioid receptor agonists studied with place and taste preference conditioning. Psychopharmacology (Berl) 86:274–280
Negus SS (2004) 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) 176:204–213
Negus SS, Rice KC (2009) Mechanisms of withdrawal-associated increases in heroin self-administration: pharmacologic modulation of heroin vs food choice in heroin-dependent rhesus monkeys. Neuropsychopharmacology 34:899–911
Negus SS, Henriksen SJ, Mattox A, Pasternak GW, Portoghese PS, Takemori AE, Weinger MB, Koob GF (1993) Effect of antagonists selective for mu, delta and kappa opioid receptors on the reinforcing effects of heroin in rats. J Pharmacol Exp Ther 265:1245–1252
Negus SS, Mello NK, Portoghese PS, Lin CE (1997) Effects of kappa opioids on cocaine self-administration by rhesus monkeys. J Pharmacol Exp Ther 282:44–55
Nestby P, Schoffelmeer AN, Homberg JR, Wardeh G, De Vries TJ, Mulder AH, Vanderschuren LJ (1999) Bremazocine reduces unrestricted free-choice ethanol self-administration in rats without affecting sucrose preference. Psychopharmacology (Berl) 142:309–317
Nestler EJ (2001) Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2:119–128
Nestler EJ (2004) Molecular mechanisms of drug addiction. Neuropharmacology 47(Suppl 1):24–32
Newton SS, Thome J, Wallace TL, Shirayama Y, Schlesinger L, Sakai N, Chen J, Neve R, Nestler EJ, Duman RS (2002) Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect. J Neurosci 22:10883–10890
Nikolarakis K, Pfeiffer A, Stalla GK, Herz A (1987) The role of CRF in the release of ACTH by opiate agonists and antagonists in rats. Brain Res 421:373–376
Nock B, Rajpara A, O’Connor LH, Cicero TJ (1988) Autoradiography of [3H]U-69593 binding sites in rat brain: evidence for kappa opioid receptor subtypes. Eur J Pharmacol 154:27–34
O’Dell LE, Roberts AJ, Smith RT, Koob GF (2004) Enhanced alcohol self-administration after intermittent versus continuous alcohol vapor exposure. Alcohol Clin Exp Res 28:1676–1682
O’Dell LE, Chen SA, Smith RT, Specio SE, Balster RL, Paterson NE, Markou A, Zorrilla EP, Koob GF (2007) Extended access to nicotine self-administration leads to dependence: Circadian measures, withdrawal measures, and extinction behavior in rats. J Pharmacol Exp Ther 320:180–193
Perreault ML, Graham D, Bisnaire L, Simms J, Hayton S, Szechtman H (2006) Kappa-opioid agonist U69593 potentiates locomotor sensitization to the D2/D3 agonist quinpirole: pre- and postsynaptic mechanisms. Neuropsychopharmacology 31:1967–1981
Pfeiffer A, Brantl V, Herz A, Emrich HM (1986) Psychotomimesis mediated by kappa opiate receptors. Science 233:774–776
Picker MJ (1994) Kappa agonist and antagonist properties of mixed action opioids in a pigeon drug discrimination procedure. J Pharmacol Exp Ther 268:1190–1198
Pliakas AM, Carlson RR, Neve RL, Konradi C, Nestler EJ, Carlezon WA Jr (2001) Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens. J Neurosci 21:7397–7403
Prisinzano TE, Tidgewell K, Harding WW (2005) Kappa opioids as potential treatments for stimulant dependence. Aaps J 7:E592–E599
Przewlocka B, Turchan J, Lason W, Przewlocki R (1997) Ethanol withdrawal enhances the prodynorphin system activity in the rat nucleus accumbens. Neurosci Lett 238:13–16
Rawls SM, McGinty JF (1998) Kappa receptor activation attenuates L-trans-pyrrolidine-2, 4-dicarboxylic acid-evoked glutamate levels in the striatum. J Neurochem 70:626–634
Redila VA, Chavkin C (2008) Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system. Psychopharmacology (Berl) 200:59–70
Reyes BA, Johnson AD, Glaser JD, Commons KG, Van Bockstaele EJ (2007) Dynorphin-containing axons directly innervate noradrenergic neurons in the rat nucleus locus coeruleus. Neuroscience 145:1077–1086
Richards ML, Sadee W (1985) In vivo binding of benzomorphans to mu, delta and kappa opioid receptors: comparison with urine output in the rat. J Pharmacol Exp Ther 233:425–432
Rosenbaum JS, Holford NH, Sadee W (1985) In vivo receptor binding of opioid drugs at the mu site. J Pharmacol Exp Ther 233:735–740
Rossier J (1982) Opioid peptides have found their roots. Nature 298:221–222
Rossier J, Chapouthier G (1982) Brain opiates. Endeavour 6:168–176
Schenk S, Partridge B (2001) Effect of the kappa-opioid receptor agonist, U69593, on reinstatement of extinguished amphetamine self-administration behavior. Pharmacol Biochem Behav 68:629–634
Schenk S, Partridge B, Shippenberg TS (1999) U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking. Psychopharmacology (Berl) 144:339–346
Schenk S, Partridge B, Shippenberg TS (2000) Reinstatement of extinguished drug-taking behavior in rats: effect of the kappa-opioid receptor agonist, U69593. Psychopharmacology (Berl) 151:85–90
Schenk S, Partridge B, Shippenberg TS (2001) Effects of the kappa-opioid receptor agonist, U69593, on the development of sensitization and on the maintenance of cocaine self-administration. Neuropsychopharmacology 24:441–450
Schlussman SD, Zhou Y, Bailey A, Ho A, Kreek MJ (2005) Steady-dose and escalating-dose “binge” administration of cocaine alter expression of behavioral stereotypy and striatal preprodynorphin mRNA levels in rats. Brain Res Bull 67:169–175
Schwarzer C (2009) 30 years of dynorphins - new insights on their functions in neuropsychiatric diseases. Pharmacol Ther
Shippenberg TS (2009) The dynorphin/kappa opioid receptor system: a new target for the treatment of addiction and affective disorders? Neuropsychopharmacology 34:247
Shippenberg TS, Herz A (1986) Differential effects of mu and kappa opioid systems on motivational processes. NIDA Res Monogr 75:563–566
Shippenberg TS, Herz A (1988) Motivational effects of opioids: influence of D-1 versus D-2 receptor antagonists. Eur J Pharmacol 151:233–242
Shippenberg TS, LeFevour A, Heidbreder C (1996) kappa-Opioid receptor agonists prevent sensitization to the conditioned rewarding effects of cocaine. J Pharmacol Exp Ther 276:545–554
Shippenberg TS, LeFevour A, Thompson AC (1998) Sensitization to the conditioned rewarding effects of morphine and cocaine: differential effects of the kappa-opioid receptor agonist U69593. Eur J Pharmacol 345:27–34
Shippenberg TS, Chefer VI, Zapata A, Heidbreder CA (2001) Modulation of the behavioral and neurochemical effects of psychostimulants by kappa-opioid receptor systems. Ann N Y Acad Sci 937:50–73
Shippenberg TS, Zapata A, Chefer VI (2007) Dynorphin and the pathophysiology of drug addiction. Pharmacol Ther 116:306–321
Shirayama Y, Ishida H, Iwata M, Hazama GI, Kawahara R, Duman RS (2004) Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like effects. J Neurochem 90:1258–1268
Simonin F, Valverde O, Smadja C, Slowe S, Kitchen I, Dierich A, Le Meur M, Roques BP, Maldonado R, Kieffer BL (1998) Disruption of the kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective kappa-agonist U-50, 488H and attenuates morphine withdrawal. EMBO J 17:886–897
Smith MA, Cole KT, Gergans SR, Iordanou JC, Lyle MA, Schmidt KT (2008) Effects of environmental enrichment on sensitivity to mu, kappa, and mixed-action opioids in female rats. Physiol Behav 94:563–568
Solecki W, Ziolkowska B, Krowka T, Gieryk A, Filip M, Przewlocki R (2009) Alterations of prodynorphin gene expression in the rat mesocorticolimbic system during heroin self-administration. Brain Res 1255:113–121
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 89:2046–2050
Spanagel R, Almeida OF, Bartl C, Shippenberg TS (1994) Endogenous kappa-opioid systems in opiate withdrawal: role in aversion and accompanying changes in mesolimbic dopamine release. Psychopharmacology (Berl) 115:121–127
Staley JK, Rothman RB, Rice KC, Partilla J, Mash DC (1997) Kapp a2 opioid receptors in limbic areas of the human brain are upregulated by cocaine in fatal overdose victims. J Neurosci 17:8225–8233
Suh HW, Song DK, Huh SO, Kim YH (2000) Involvement of dynorphin in immobilization stress-induced antinociception in the mouse. Eur Neuropsychopharmacol 10:407–413
Takahashi M, Senda T, Tokuyama S, Kaneto H (1990) Further evidence for the implication of a kappa-opioid receptor mechanism in the production of psychological stress-induced analgesia. Jpn J Pharmacol 53:487–494
Takemori AE, Ho BY, Naeseth JS, Portoghese PS (1988) Nor-binaltorphimine, a highly selective kappa-opioid antagonist in analgesic and receptor binding assays. J Pharmacol Exp Ther 246:255–258
Tao R, Auerbach SB (2002) Opioid receptor subtypes differentially modulate serotonin efflux in the rat central nervous system. J Pharmacol Exp Ther 303:549–556
Tao R, Auerbach SB (2005) mu-Opioids disinhibit and kappa-opioids inhibit serotonin efflux in the dorsal raphe nucleus. Brain Res 1049:70–79
Todtenkopf MS, Marcus JF, Portoghese PS, Carlezon WA Jr (2004) Effects of kappa-opioid receptor ligands on intracranial self-stimulation in rats. Psychopharmacology (Berl) 172:463–470
Tomasiewicz HC, Todtenkopf MS, Chartoff EH, Cohen BM, Carlezon WA Jr (2008) The kappa-opioid agonist U69,593 blocks cocaine-induced enhancement of brain stimulation reward. Biol Psychiatry
Tortella FC, Robles L, Holaday JW (1986) U50, 488, a highly selective kappa opioid: anticonvulsant profile in rats. J Pharmacol Exp Ther 237:49–53
Tortella FC, Robles L, Mosberg HI (1987) Evidence for mu opioid receptor mediation of enkephalin-induced electroencephalographic seizures. J Pharmacol Exp Ther 240:571–577
Tsuji M, Takeda H, Matsumiya T, Nagase H, Narita M, Suzuki T (2001) The novel kappa-opioid receptor agonist TRK-820 suppresses the rewarding and locomotor-enhancing effects of morphine in mice. Life Sci 68:1717–1725
Valdez GR, Platt DM, Rowlett JK, Ruedi-Bettschen D, Spealman RD (2007) Kappa agonist-induced reinstatement of cocaine seeking in squirrel monkeys: a role for opioid and stress-related mechanisms. J Pharmacol Exp Ther 323:525–533
Vonvoigtlander PF, Lahti RA, Ludens JH (1983) U-50, 488: a selective and structurally novel non-Mu (kappa) opioid agonist. J Pharmacol Exp Ther 224:7–12
Walker BM, Koob GF (2008) Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence. Neuropsychopharmacology 33:643–652
Walsh SL, Geter-Douglas B, Strain EC, Bigelow GE (2001) Enadoline and butorphanol: evaluation of kappa-agonists on cocaine pharmacodynamics and cocaine self-administration in humans. J Pharmacol Exp Ther 299:147–158
Watson SJ, Khachaturian H, Akil H, Coy DH, Goldstein A (1982) Comparison of the distribution of dynorphin systems and enkephalin systems in brain. Science 218:1134–1136
Wee S, Orio L, Ghirmai S, Cashman JR, Koob GF (2009) Inhibition of kappa opioid receptors attenuated increased cocaine intake in rats with extended access to cocaine. Psychopharmacology (Berl)
White JM, Holtzman SG (1983) Further characterization of the three-choice morphine, cyclazocine and saline discrimination paradigm: opioids with agonist and antagonist properties. J Pharmacol Exp Ther 224:95–99
Williams KL, Woods JH (1998) Oral ethanol-reinforced responding in rhesus monkeys: effects of opioid antagonists selective for the mu-, kappa-, or delta-receptor. Alcohol Clin Exp Res 22:1634–1639
Wittmann W, Schunk E, Rosskothen I, Gaburro S, Singewald N, Herzog H, Schwarzer C (2009) Prodynorphin-derived peptides are critical modulators of anxiety and regulate neurochemistry and corticosterone. Neuropsychopharmacology 34:775–785
Woolley JD, Lee BS, Kim B, Fields HL (2007) Opposing effects of intra-nucleus accumbens mu and kappa opioid agonists on sensory specific satiety. Neuroscience 146:1445–1452
Xi ZX, Fuller SA, Stein EA (1998) Dopamine release in the nucleus accumbens during heroin self-administration is modulated by kappa opioid receptors: an in vivo fast-cyclic voltammetry study. J Pharmacol Exp Ther 284:151–161
Yamada K, Nabeshima T (1995) Stress-induced behavioral responses and multiple opioid systems in the brain. Behav Brain Res 67:133–145
Young GA, Khazan N (1983) Self-administration of ketocyclazocine and ethylketocyclazocine by the rat. Pharmacol Biochem Behav 19:711–713
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) 172:422–429
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) 179:551–558
Zimmer A, Valjent E, Konig M, Zimmer AM, Robledo P, Hahn H, Valverde O, Maldonado R (2001) Absence of delta-9-tetrahydrocannabinol dysphoric effects in dynorphin-deficient mice. J Neurosci 21:9499–9505
Acknowledgments
We gratefully acknowledge the assistance of Mike Arends in the preparation of the manuscript. We thank Dr. Brendan Walker for discussions and stimulating our interest in the kappa opioid system. This is publication number 20445 from The Scripps Research Institute. Preparation of this manuscript was supported by National Institutes of Health grants DA04043 (G.F.K.), DA04398 (G.F.K.) and DA025785 (S.W.) from the National Institute on Drug Abuse.
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Wee, S., Koob, G.F. The role of the dynorphin–κ opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology 210, 121–135 (2010). https://doi.org/10.1007/s00213-010-1825-8
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DOI: https://doi.org/10.1007/s00213-010-1825-8