, Volume 213, Issue 4, pp 735–744 | Cite as

Desensitization of δ-opioid receptors in nucleus accumbens during nicotine withdrawal

  • Michael J. McCarthy
  • Hailing Zhang
  • Norton H. Neff
  • Maria HadjiconstantinouEmail author
Original Investigation



The synthesis and release of met-enkephalin and β-endorphin, endogenous ligands for δ-opioid peptide receptors (DOPrs), are altered following nicotine administration and may play a role in nicotine addiction.


To investigate the consequences of altered opioidergic activity on DOPr expression, coupling, and function in striatum during early nicotine withdrawal.


Mice received nicotine-free base, 2 mg/kg, or saline, subcutaneously (s.c.), four times daily for 14 days and experiments performed at 24, 48, and 72 h after drug discontinuation. DOPr binding and mRNA were evaluated by [3 H]naltrindole autoradiography and in situ hybridization. DOPr coupling and function were investigated by agonist pCl-DPDPE-stimulated [35 S]GTPγS binding autoradiography and inhibition of adenylyl cyclase activity.


During nicotine withdrawal DOPr binding was unaltered in caudate/putamen (CPu) and nucleus accumbens (NAc) shell and core. Receptor mRNA was slightly increased in the shell at 72 h, but significant elevations were observed in prefrontal cortex and hippocampus. pCl-DPDPE-stimulated [35 S]GTPγS binding was attenuated in NAc, but not CPu. In the shell, binding was decreased by 48 h and remained decreased over 72 h; while in the core, significant reduction was seen at 72 h. Basal adenylyl cyclase activity was suppressed in striatum at 24 h, but recovered by 48 h. DOPr stimulation with pCl-DPDPE failed to inhibit adenylyl cyclase activity at 24 h and produced attenuated responses at 48 and 72 h.


These observations suggest that DOPr coupling and function are impaired in the NAc during nicotine withdrawal. DOPr desensitization might be involved in the affective component of nicotine withdrawal.


Nicotine withdrawal δ-Opioid receptors Binding mRNA [35S]GTPγS binding Adenylyl cyclase Desenstitization Caudate/putamen Nucleus accumbens 


  1. Angulo JA, McEwen BS (1994) Molecular aspects of neuropeptide regulation and function in the corpus striatum and nucleus accumbens. Brain Res Rev 19:1–28CrossRefPubMedGoogle Scholar
  2. Balerio GN, Aso E, Maldonado R (2005) Involvement of the opioid system in the effects induced by nicotine on anxiety-like behaviour in mice. Psychopharmacology 181:260–269CrossRefPubMedGoogle Scholar
  3. Barrot M, Olivier JDA, Perrotti LI, DiLeone RJ, Berton O, Eisch AJ, Impey S, Storm DR, Neve RL, Yin JC, Zachariou V, Nestler EJ (2002) CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli. Proc Natl Acad Sci USA 99:11435–11440CrossRefPubMedGoogle Scholar
  4. Bausch SB, Patterson TA, Appleyard SM, Chavkin C (1995) Immunohistological localization of delta opioid receptors in mouse brain. J Chem Neuroanat 8:175–189CrossRefPubMedGoogle Scholar
  5. Berrendero F, Kieffer BL, Maldonado R (2002) Attenuation of nicotine-induced antinociception, rewarding effects, and dependence in μ-opioid receptor knock-out mice. J Neurosci 22:10935–10940PubMedGoogle Scholar
  6. Berrendero F, Mendizabal V, Robledo P, Galeote L, Bilkei-Gorzo A, Zimmer A, Maldonado R (2005) Nicotine-induced antinociception, rewarding effects, and physical dependence are decreased in mice lacking the preproenkephalin gene. J Neurosci 25:1103–1112CrossRefPubMedGoogle Scholar
  7. Berridge KC, Robinson TE, Aldridge JW (2009) Dissecting components of reward: ‘liking’, ‘wanting’, and learning. Curr Opin Pharmacol 9:65–73CrossRefPubMedGoogle Scholar
  8. Bevins RA, Besheer J (2005) Novelty reward as a measure of anhedonia. Neurosci Biobehav Rev 29:707–714CrossRefPubMedGoogle Scholar
  9. Boyadjieva NI, Sarkar DK (1997) The secretory response of hypothalamic β-endoprhin neurons to acute and chronic nicotine treatment and following nicotine withdrawal. Life Sci 61:59–66CrossRefGoogle Scholar
  10. Broom DC, Jutkiewicz EM, Folk JE, Traynor JR, Rice KC, Woods JH (2002) Nonpeptide delta-opioid receptor agonists reduce immobility in the forced swim assay in rats. Neuropsychopharmacology 26:744–755CrossRefPubMedGoogle Scholar
  11. Cahill CM, McClellan KA, Morinville A, Hoffert C, Hubatsch D, O’Donnell D, Beaudet A (2001) Immunohistochemical distribution of delta opioid receptors in the rat central nervous system: evidence for somatodendritic labeling and antigen-specific cellular compartmentalization. J Comp Neurol 440:65–84CrossRefPubMedGoogle Scholar
  12. Chan K, Brodsky M, Davis T, Franklin S, Inturrisi CE, Yoburn BC (1995) The effect of the irreversible mu-opioid receptor antagonist clocinnamox on morphine potency, receptor binding and receptor mRNA. Eur J Pharmacol 287:135–143CrossRefPubMedGoogle Scholar
  13. Corbett AD, Paterson SJ, Kostrelitz HW (1993) Selectivity of ligands for opioid receptors. In: Hertz A (ed) Opioids I, vol 104/1. Springer, Berlin, pp 645–679Google Scholar
  14. Costall B, Kelly ME, Naylor RJ, Onaivi ES (1989) The actions of nicotine and cocaine in a mouse model of anxiety. Pharmacol Biochem Behav 33:197–203CrossRefPubMedGoogle Scholar
  15. del Arbol JL, Muñoz JR, Ojeda L, Cascales L, Rico Irles J, Miranda MT, Ruiz Requena ME, Aguirre JC (2000) Plasma concetrations of beta-endoprhin in smokers who consume different numbers of cigarettes per day. Pharmacol Biochem Behav 67:25–28CrossRefPubMedGoogle Scholar
  16. Dhatt R, Gudehithlu KP, Wemlinger TA, Tejwani GA, Neff NH, Hadjiconstantinou M (1995) Preproenkephalin mRNA and methionine-enkephalin content are increased in mouse striatum after treatment with nicotine. J Neurochem 64:1878–1883CrossRefPubMedGoogle Scholar
  17. Duchemin A-M, Zhang H, Neff NH, Hadjiconstantinou M (2009) Increased expression of VMAT2 in dopaminergic neurons during nicotine withdrawal. Neurosci Lett 467:182–186CrossRefPubMedGoogle Scholar
  18. Epping-Jordan MP, Watkins SS, Koob GF, Markou A (1998) Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393:76–79CrossRefPubMedGoogle Scholar
  19. Filliol D, Ghozland S, Scluba J, Martin M, Matthes HW, Simonin F, Befort K, Gavériaux-Ruff C, Dierich A, LeMeur M, Valverde O, Maldonado R, Kieffer BL (2000) Mice deficient for δ- and μ-opioid receptors exhibit opposing alterations of emotional responses. Nat Genet 25:195–200CrossRefPubMedGoogle Scholar
  20. Foulds J, Stapelton JA, Bell N, Swettenham J, Jarvis MJ, Russell MAH (1997) Mood and physiological effects of subcutaneous nicotine in smokers and never smokers. Drug Alcohol Depend 44:105–115CrossRefPubMedGoogle Scholar
  21. 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 12:615–625CrossRefPubMedGoogle Scholar
  22. Hadjiconstantinou M, Duchemin A-M, Zhang H, Neff NH (2010) Enhanced dopamine transporter function in striatum during nicotine withdrawal. Synapse. doi: 10.1002/syn.20820 [Epub 2010, May 19]Google Scholar
  23. Happe HK, Bylund DB, Murrin LC (2001) Agonist-stimulated [35 S]GTPgammaS autoradiography: optimization for high sensitivity. Eur J Pharmacol 422:1–13CrossRefPubMedGoogle Scholar
  24. Harrison C, Traynor JR (2003) The [35 S]GTPγS binding assay: approaches and applications in pharmacology. Life Sci 74:489–508CrossRefPubMedGoogle Scholar
  25. Hayward MD, Pintar JE, Low MJ (2002) Selective reward deficit in mice lacking β-endorphin and enkephalin. J Neurosci 22:8251–8258PubMedGoogle Scholar
  26. Heishman SJ, Hennigfield JF (2000) Tolerance to repeated nicotine administration on performance, subjective, and physiological response to nonsmokers. Psychopharmacology 152:321–333CrossRefPubMedGoogle Scholar
  27. Houdi AA, Pierzchala K, Marson L, Palkovits M, Van Loon GR (1991) Nicotine-induced alteration of Tyr-Gly-Gly and Met-enkephalin in discrete brain nuclei reflects altered enkephalin neuron activity. Peptides 12:161–166CrossRefPubMedGoogle Scholar
  28. Houdi AA, Dasgupta R, Kindy MS (1998) Effect of nicotine use and withdrawal on brain preproenkephalin A mRNA. Brain Res 799:257–263CrossRefPubMedGoogle Scholar
  29. Hughes JR (2007) Effects of abstinence from tobacco: valid symptoms and time course. Nicotine Tob Res 9:309–313CrossRefGoogle Scholar
  30. Ise Y, Narita M, Nagase H, Suzuki T (2000) Modulation of opioidergic system on mecamylamine-precipitated nicotine-withdrawal aversion in rats. Psychopharmacology 151:49–54CrossRefPubMedGoogle Scholar
  31. Ismayilova N, Shoaib M (2010) Alteration of intravenous nicotine self-administration by opioid receptor agonists and antagonists in rats. Psychopharmacology. doi: 10.1007/s00213-010-1845.4 [Epub 2010, Apr 17]PubMedGoogle Scholar
  32. Isola R, Vogelsberg V, Wemlinger TA, Neff NH, Hadjiconstantinou M (1999) Nicotine abstinence in the mouse. Brain Res 850:189–196CrossRefPubMedGoogle Scholar
  33. Isola R, Duchemin A-M, Tejwani GA, Neff NH, Hadjiconstantinou M (2000) Glutamate receptors participate in the nicotine-induced changes of met-enkephalin in striatum. Brain Res 878:72–78CrossRefPubMedGoogle Scholar
  34. Isola R, Zhang H, Duchemin A-M, Tejwani GA, Neff NH, Hadjiconstantinou M (2002) Met-enkephalin and preproenkephalin mRNA changes in the striatum of the nicotine abstinense mouse. Neurosci Lett 325:67–71CrossRefPubMedGoogle Scholar
  35. Isola R, Zhang H, Tejwani GA, Neff NH, Hadjiconstantinou M (2008) Dynorphin and prodynorphin mRNA changes in the striatum during nicotine withdrawal. Synapse 62:448–455CrossRefPubMedGoogle Scholar
  36. Isola R, Zhang H, Tejwani GA, Neff NH, Hadjiconstantinou M (2009) Acute nicotine changes dynorphin and prodynorphin mRNA in the striatum. Psychopharmacology 201:507–516CrossRefPubMedGoogle Scholar
  37. Izenwasser S, Buzas B, Cox BM (1993) Differential regulation of adenylyl cyclase activity by mu and delta opioids in rat caudate-putamen and nucleus accumbens. J Pharmacol Exp Ther 267:145–152PubMedGoogle Scholar
  38. Johnson PM, Hollander JA, Kenny PJ (2008) Decreased brain reward function during nicotine withdrawal in C57BL6 mice: evidence from intracranial self-stimulation (ICSS) studies. Pharmacol Biochem Behav 90:409–415CrossRefPubMedGoogle Scholar
  39. Kelly MD, Hill RG, Borsodi A, Toth G, Kitchen I (1998) Weaning-induced development of delta-opioid receptors in rat brain: differential effects of guanine nucleotides and sodium upon ligand-receptor recognition. Br J Pharmacol 125:979–986CrossRefPubMedGoogle Scholar
  40. Kitchen I, Slowe SJ, Matthes HWD, Kieffer B (1997) Quantitative autoradiographic mapping of mu- delta- and kappa-opioid receptors in knockout mice lacking the mu opioid receptor gene. Brain Res 778:73–88CrossRefPubMedGoogle Scholar
  41. Lecoq I, Maria N, Jauzac PH, Allouche S (2004) Different regulation of human δ-opioid receptors by SNC-80[(+)-4-[αR)-α-((2S, 5R)-4-Allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide] and endogenous enkephalins. J Pharmacol Exp Ther 310:666–677CrossRefPubMedGoogle Scholar
  42. Le Merrer J, Becker JAJ, Befort K, Kieffer BL (2009) Reward processing by the opioid system in the brain. Physiol Rev 89:1379–1412CrossRefPubMedGoogle Scholar
  43. Malin DH, Lake JR, Newlin-Maultsby P, Roberts LK, Lanier JG, Carter VA, Cunningham JS, Wilson OB (1992) Rodent model of nicotine abstinence syndrome. Pharmacol Biochem Behav 43:779–784CrossRefPubMedGoogle Scholar
  44. Malin DH, Lake RJ, Carter VA, Cunningham JS, Wilson OB (1993) Naloxone precipitates nicotine abstinence syndrome in the rat. Psychopharmacology 112:339–342CrossRefPubMedGoogle Scholar
  45. Marie N, Aguila B, Allouche S (2006) Tracking the opioid receptors on the way of desensitization. Cell Signal 18:1815–1833CrossRefPubMedGoogle Scholar
  46. Markou A, Kosten TR, Koob GF (1998) Neurobiological similarities in depression and drug dependence: a self mediation hypothesis. Neuropsychopharmacology 18:135–174CrossRefPubMedGoogle Scholar
  47. Marty MA, Ervin VG, Cornell K, Zgomblick HM (1985) Effects of nicotine on alpha-endorphin, beta-MSH and ACTH secretion by isolated perfused mouse brains and pituitary glands, in vitro. Pharmacol Biochem Behav 22:317–325CrossRefPubMedGoogle Scholar
  48. Mas Nieto M, Guen SLE, Kieffer BL, Roques BP, Noble F (2005) Physiological control of emotion-related behaviors by endogenous enkephalins involves essentially the delta opioid receptors. Neuroscience 135:305–313CrossRefPubMedGoogle Scholar
  49. McCarthy MJ, Zhang H, Neff NH, Hadjiconstantinou M (2010) Nicotine withdrawal and κ-opioid receptors. Psychopharmacology 210:221–229CrossRefPubMedGoogle Scholar
  50. Paxinos G, Franklin BL (2001) The mouse brain in stereotaxic coordinates. Academic, San DiegoGoogle Scholar
  51. Perrine SA, Hoshaw BA, Unterwald EM (2006) Delta opioid receptor ligands modulate anxiety-like behaviors in the rat. Br J Pharmacol 147:864–872CrossRefPubMedGoogle Scholar
  52. Pierzchala K, Houdi AA, Van Loon GR (1987) Nicotine induced alteration in brain regional concentration of cryptic Met- and Leu-enkephalin. Peptides 8:1035–1043CrossRefPubMedGoogle Scholar
  53. Pomerleau OF (1998) Endogenous opioids and smoking: a review of progress and problems. Psychoneuroendocrinology 23:115–130CrossRefPubMedGoogle Scholar
  54. Pradhan AAA, Becker JAJ, Scherrer G, Tryoen-Toth P, Filliol D, Matifas A, Massotte D, Gaveraux-Ruff C, Kieffer B (2009) In vivo delta opioid receptor internalization controls behavioral effects of agonists. PLoS ONE 4(5):e5425. doi: 10.1371/journal.pone.0005425 CrossRefPubMedGoogle Scholar
  55. Preus TM (1995) Do rats have prefrontal cortex? The Rose–Woolsey–Akert program reconsidered. J Cogn Neurosci 7:1–24CrossRefGoogle Scholar
  56. Rasmussen DD (1998) Effects of chronic nicotine treatment and withdrawal on hypothalamic proopiomelanocortin gene expression and neuroendocrine regulation. Psychoneuroendocrinology 23:245–259CrossRefPubMedGoogle Scholar
  57. Rosecrans JA, Hendry JS, Hong JS (1985) Biphasic effects of chronic nicotine treatment on hypothalamic immunoreactive beta-endorphin in the mouse. Pharmacol Biochem Behav 23:141–143CrossRefPubMedGoogle Scholar
  58. Saitoh A, Kimura Y, Suzuki T, Kawai K, Nagase H, Kamei J (2004) Potential anxiolytic and antidepressant-like activities of SNC80, a selective delta-opioid agonist, in behavioral models in rodents. J Pharmacol Sci 95:374–380CrossRefPubMedGoogle Scholar
  59. Saitoh A, Yoshikawa Y, Onodera K, Kamei J (2005) Role of δ-opioid receptor subtypes in anxiety-related behaviors in the elevated plus-maze in rats. Psychopharmacology 182:327–334CrossRefPubMedGoogle Scholar
  60. Shippenberg TS, Bals-Kubik R, Hertz A (1987) Motivational properties of opioids: evidence that an activation of δ-receptors mediates reinforcement processes. Brain Res 436:234–239CrossRefPubMedGoogle Scholar
  61. Shippenberg TS, LeFevour A, Chefer VI (2008) Targeting endogenous mu- and delta-opioid receptor systems for the treatment of drug addiction. CNS Neurol Disord Drug Targets 7:442–453CrossRefPubMedGoogle Scholar
  62. Shirayama Y, Chaki S (2006) Neurochemistry of the nucleus accumbens and its relevance to depression and antidepressant action in rodents. Curr Neuropharmacol 4:277–291CrossRefPubMedGoogle Scholar
  63. Shram MJ, Siu ECK, Li Z, Tyndale RF, Le AD (2008) Interactions between age and the aversive effects of nicotine withdrawal under mecamylamine-precipitated and spontaneous conditions in male Wistar rats. Psychopharmacology 198:181–190CrossRefPubMedGoogle Scholar
  64. Sim LJ, Selley DE, Childers SR (1995) In vitro autoradiography of receptor-mediated G-proteins in rat brain by agonist-stimulated guanylyl 5′-[gamma-[35S]thio]triphosphate binding. Proc Natl Acad Sci USA 92:7242–7246CrossRefPubMedGoogle Scholar
  65. Skoubis PD, Lam HA, Shoblock J, Narayanan S, Maidment NT (2005) Endogenous enkephalins, not endorphins, modulate basal hedonic state in mice. Eur J Neurosci 21:1379–1384CrossRefPubMedGoogle Scholar
  66. Stoker AK, Semenova S, Markou A (2008) Affective and somatic aspects of spontaneous and precipitated nicotine withdrawal in C57BL/6J and BALB/cByJ mice. Neuropharmacology 54:1223–1232CrossRefPubMedGoogle Scholar
  67. Suzuki T, Ise Y, Tsuda M, Maeda J, Misawa M (1996a) Mecamylamine-precipitated nicotine withdrawal aversion in rats. Eur J Pharmacol 314:281–284CrossRefPubMedGoogle Scholar
  68. Suzuki T, Tsuji M, Mori T, Misawa M, Nagase H (1996b) The effects of dopamine D1 and D2 receptor antagonists in the rewarding effects of δ1 and δ2 opioid receptor agonists in mice. Psychopharmacology 124:211–218CrossRefPubMedGoogle Scholar
  69. Svingos AL, Clarke CL, Pickel VM (1998) Cellular sites for activation of δ-opioid receptors in the rat nucleus accumbens shell: relationship with met-enkephalin. J Neurosci 18:1923–1933PubMedGoogle Scholar
  70. Svingos AL, Clarke CL, Pickel VM (1999) Localization of the δ-opioid receptor and dopamine transporter in the nucleus accumbens shell: implications for opiate and psychostimulant cross-sensitization. Synapse 34:1–10CrossRefPubMedGoogle Scholar
  71. Trigo JM, Zimmer A, Maldonado R (2009) Nicotine anxiogenic and rewarding effects are decreased in mice lacking β-endorphin. Neuropharmacology 56:1147–1153CrossRefPubMedGoogle Scholar
  72. Varga EV, Navratilova E, Stropova D, Jambrosic J, Roeske W, Yamamura H (2004) Agonist-specific regulation of δ-opioid receptor. Life Sci 76:599–612CrossRefPubMedGoogle Scholar
  73. Vergura R, Balboni G, Spagnolo B, Gavioli E, Lambert DG, McDonald J, Trapella C, Lazarus LH, Regoli D, Guerrini R, Salvadori S, Caló G (2008) Anxiolytic and antidepressant-like activities of H-Dmt-Tic-NH-CH(CH2-COOH)-Bid (UFP-512) a novel selective delta opioid receptor agonist. Peptides 29:93–103CrossRefPubMedGoogle Scholar
  74. Waldhoer M, Barlett SE, Whistler JL (2004) Opioid receptors. Annu Rev Biochem 73:953–990CrossRefPubMedGoogle Scholar
  75. Wallace D, Han M-H, Graham DL, Green TA, Vialou V, Iñiguez SD, Cao JL, Kirk A, Chakravarty S, Kumar A, Krishnan V, Neve RL, Cooper DC, Bolaños CA, Barrot M, McClung CA, Nestler EJ (2009) CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nat Neurosci 12:200–209CrossRefPubMedGoogle Scholar
  76. Wang H, Pickel VM (2001) Preferential cytoplasmic localization of δ-opioid receptors in rat striatal patches: comparison with plasmalemmal μ-opioid receptors. J Neurosci 21:3242–3250PubMedGoogle Scholar
  77. Wang Y, Van Bockstaele EJ, Liu-Chen L-Y (2008) In vivo trafficking of endogenous opioid receptors. Life Sci 83:693–699CrossRefPubMedGoogle Scholar
  78. Watkins SS, Stinus L, Koob GF, Markou A (2000) Reward and somatic changes during precipitated nicotine withdrawal in rats: centrally and peripherally mediated effects. J Pharmacol Exp Ther 292:1053–1064PubMedGoogle Scholar
  79. Wewers ME, Tejwani GA, Anderson J (1994) Plasma nicotine, plasma beta-endorphin and mood states during periods of chronic smoking, abstinence and nicotine replacement. Psychopharmacology 116:98–102CrossRefPubMedGoogle Scholar
  80. Zaniewska M, McCreary AC, Wydra K, Filip M (2010) Effects of serotonin (5-HT)2 receptor ligands on depression-like behavior during nicotine withdrawal. Neuropharmacology 58:1140–1146CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Michael J. McCarthy
    • 1
  • Hailing Zhang
    • 1
  • Norton H. Neff
    • 1
    • 2
  • Maria Hadjiconstantinou
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Psychiatry, Division of Molecular NeuropsychopharmacologyThe Ohio State University College of MedicineColumbusUSA
  2. 2.Department of PharmacologyThe Ohio State University College of MedicineColumbusUSA
  3. 3.Department of Psychiatry, College of MedicineOhio State UniversityColumbusUSA

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