, Volume 232, Issue 10, pp 1747–1753 | Cite as

Effect of morphine on the persistence of long-term memory in rats

  • Gerusa Paz Porto
  • Laura Hautrive Milanesi
  • Maribel Antonello Rubin
  • Carlos Fernando MelloEmail author
Original Investigation



Current evidence suggests that pharmacological manipulation around 12 h after training alters the persistence of long-term memory. However, no study has addressed whether opioids modulate the persistence of fear. The current study examined whether morphine alters the persistence of the memory of contextual fear conditioning.


Male adult Wistar rats were injected with saline (NaCl 0.9 %, intraperitoneally (i.p.)) or morphine (3 and/or 10 mg/kg, i.p.) 6, 9, 12, or 24 h post-training and tested 2 or 7 days after training, when freezing responses were assessed. The involvement of state dependence and opioid receptors in the effect of morphine was investigated by respectively injecting naloxone (1 mg/kg, i.p.) 30 min before morphine, and morphine (10 mg/kg, i.p.) 30 min before testing.


Morphine (10 mg/kg, i.p., 12 h post-training) did not alter freezing to context in animals tested 2 days after training but impaired freezing to context when testing was carried out 7 or 14 days after training. Morphine (10 mg/kg, i.p.) administration 6, 9, or 24 h post-training did not alter freezing measured 2 or 7 days after training. Pre-test morphine improved recall but did not alter the deleterious effect of 12 h post-training morphine. The deleterious effect of morphine was prevented by naloxone, indicating that opioid receptors are involved in this effect.


Our findings indicate an inhibitory role for opioid receptors in memory persistence. This is relevant from both the experimental and clinical point of views, since it may have implications for the prevention of post-traumatic stress disorder (PTSD).


Morphine Long-term memory Persistence Fear conditioning Rat 



This work was supported by grants from CAPES, CNPq, and FAPERGS, Brazil. CFM and MAR are recipients of CNPq productivity fellowships. LHM is the recipient of a PIBIC/CNPq/UFSM fellowship.


  1. Aguilar MA, Minarro J, Simon VM (1998) Dose-dependent impairing effects of morphine on avoidance acquisition and performance in male mice. Neurobiol Learn Mem 69:92–105CrossRefPubMedGoogle Scholar
  2. Beatty WW (1983) Opiate antagonists, morphine and spatial memory in rats. Pharmacol Biochem Behav 19:397–401CrossRefPubMedGoogle Scholar
  3. Bekinschtein P, Cammarota M, Igaz LM, Bevilaqua LR, Izquierdo I, Medina JH (2007) Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase in the hippocampus. Neuron 53:261–77CrossRefPubMedGoogle Scholar
  4. Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, Izquierdo I, Medina JH (2008) BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A 105:2711–2716CrossRefPubMedCentralPubMedGoogle Scholar
  5. Bekinschtein P, Katche C, Slipczuk L, Gonzalez C, Dorman G, Cammarota M, Izquierdo I, Medina JH (2010) Persistence of long-term memory storage: new insights into its molecular signatures in the hippocampus and related structures. Neurotox Res 18:377–385CrossRefPubMedGoogle Scholar
  6. Bermudez-Rattoni F, Introini-Collison I, Coleman-Mesches K, McGaugh JL (1997) Insular cortex and amygdala lesions induced after aversive training impair retention: effects of degree of training. Neurobiol Learn Mem 67:57–63CrossRefPubMedGoogle Scholar
  7. Bodnar RJ (2011) Endogenous opiates and behavior: 2010. Peptides 32:2522–5252CrossRefPubMedGoogle Scholar
  8. Bruins Slot LA, Colpaert FC (1999) Opiate states of memory: Receptor mechanisms. J Neurosci 19:10520–10529PubMedGoogle Scholar
  9. Castellano C (1975) Effects of morphine and heroin on discrimination learning and consolidation in mice. Psychopharmacologia 42:235–242CrossRefPubMedGoogle Scholar
  10. Castellano C, Pavone F (1984) Effects of DL-allylglycine, alone or in combination with morphine, on passive avoidance behaviour in C57BL/6 mice. Arch Int Pharmacodyn Ther 267:141–148PubMedGoogle Scholar
  11. Castellano C, Libri V, Ammassari-Teule M (1988) The amygdala mediates the impairing effect of the selective kappa-opioid receptor agonist U-50,488 on memory in CD1 mice. Behav Brain Res 30:259–263CrossRefPubMedGoogle Scholar
  12. Castellano C, Cestari V, Cabib S, Puglisi-Allegra S (1994) The effects of morphine on memory consolidation in mice involve both D1 and D2 dopamine receptors. Behav Neural Biol 61:156–161CrossRefPubMedGoogle Scholar
  13. Davis HP, Squire LR (1984) Protein synthesis and memory: a review. Psychol Bull 96:518–559CrossRefPubMedGoogle Scholar
  14. Fanselow MS (1980) Conditioned and unconditional components of post-shock freezing. Pavlov J Biol Sci 15:177–182PubMedGoogle Scholar
  15. Farahmandfar M, Naghdi N, Karimian SM, Kadivar M, Zarrindast MR (2012) Amnesia induced by morphine in spatial memory retrieval inhibited in morphine-sensitized rats. Eur J Pharmacol 683:132–139CrossRefPubMedGoogle Scholar
  16. Galizio M, Deal M, Hawkey A, April B (2013) Working memory in the odor span task: effects of chlordiazepoxide, dizocilpine (MK801), morphine, and scopolamine. Psychopharmacol (Berl) 225:397–406Google Scholar
  17. Goeldner C, Reiss D, Wichmann J, Kieffer BL, Ouagazzal AM (2009) Activation of nociceptin opioid peptide (NOP) receptor impairs contextual fear learning in mice through glutamatergic mechanisms. Neurobiol Learn Mem 91:393–401CrossRefPubMedGoogle Scholar
  18. Holbrook TL, Galarneau MR, Dye JL, Quinn K, Dougherty AL (2010) Morphine use after combat injury in Iraq and post-traumatic stress disorder. N Engl J Med 362:110–117CrossRefPubMedGoogle Scholar
  19. Introini IB, McGaugh JL, Baratti CM (1985) Pharmacological evidence of a central effect of naltrexone, morphine, and beta-endorphin and a peripheral effect of met- and leu-enkephalin on retention of an inhibitory response in mice. Behav Neural Biol 44:434–446CrossRefPubMedGoogle Scholar
  20. Izquierdo I (1979) Effect of naloxone and morphine on various forms of memory in the rat: possible role of engogenous opiate mechanisms in memory consolidation. Psychopharmacol (Berl) 66:199–203CrossRefGoogle Scholar
  21. Izquierdo I, Cammarota M, Medina JH, Bevilaqua LR (2004) Pharmacological findings on the biochemical bases of memory processes: a general view. Neural Plast 11:159–189CrossRefPubMedCentralPubMedGoogle Scholar
  22. Izquierdo I, Bevilaqua LR, Rossato JI, Lima RH, Medina JH, Cammarota M (2008) Age-dependent and age-independent human memory persistence is enhanced by delayed posttraining methylphenidate administration. Proc Natl Acad Sci U S A 105:19504–19507CrossRefPubMedCentralPubMedGoogle Scholar
  23. Kandel ER (2001) The molecular biology of memory storage: a dialogue between genes and synapses. Science 294:1030–1038CrossRefPubMedGoogle Scholar
  24. Mariani RK, Mello CF, Rosa MM, Ceretta AP, Camera K, Rubin MA (2011) Effect of naloxone and morphine on arcaine-induced state-dependent memory in rats. Psychopharmacol (Berl) 215:483–491CrossRefGoogle Scholar
  25. McNally GP, Westbrook RF (2003) Temporally graded, context-specific retrograde amnesia and its alleviation by context preexposure: effects of postconditioning exposures to morphine in the rat. J Exp Psychol Anim Behav Process 29:130–142CrossRefPubMedGoogle Scholar
  26. McNamara RK, Skelton RW (1992) Pharmacological dissociation between the spatial learning deficits produced by morphine and diazepam. Psychopharmacol (Berl) 108:147–152CrossRefGoogle Scholar
  27. Medina JH, Bekinschtein P, Cammarota M, Izquierdo I (2008) Do memories consolidate to persist or do they persist to consolidate. Behav Brain Res 192:61–69CrossRefPubMedGoogle Scholar
  28. Miladi-Gorji H, Rashidy-Pour A, Fathollahi Y, Akhavan MM, Semnanian S, Safari M (2011) Voluntary exercise ameliorates cognitive deficits in morphine dependent rats: the role of hippocampal brain-derived neurotrophic factor. Neurobiol Learn Mem 96:479–491CrossRefPubMedGoogle Scholar
  29. Mondadori C, Waser PG (1979) Facilitation of memory processing by posttrial morphine: possible involvement of reinforcement mechanisms. Psychopharmacol (Berl) 63:297–300CrossRefGoogle Scholar
  30. Parent MB, Quiriarte GL, Cahill L, McGaugh JL (1995a) Spared retention of inhibitory avoidance learning following posttraining amygdala lesions. Behav Neurosci 109:803–807CrossRefPubMedGoogle Scholar
  31. Parent MB, West M, McGaugh JL (1995b) Memory of rats with amygdala lesions induced 30 days after footshock-motivated escape training reflects degree of original training. Behav Neurosci 108:1080–1087CrossRefGoogle Scholar
  32. Parfitt GM, Campos RC, Barbosa AK, Koth AP, Barros DM (2012) Participation of hippocampal cholinergic system in memory persistence for inhibitory avoidance in rats. Neurobiol Learn Mem 97:183–188CrossRefPubMedGoogle Scholar
  33. Ragozzino ME, Gold PE (1994) Task-dependent effects of intra-amygdala morphine injections: attenuation by intra-amygdala glucose injections. J Neurosci 14:7478–7485PubMedGoogle Scholar
  34. Roesler R, McGaugh JL (2010) Memory Consolidation. In: Le Moal M, Thompson RF (eds) Koob GF. Encyclopedia of Behavioral Neuroscience, Academic Press, Oxford, pp 206–214Google Scholar
  35. Rossato JI, Bevilaqua LR, Izquierdo I, Medina JH, Cammarota M (2009) Dopamine controls persistence of long-term memory storage. Science 325:1017–1020CrossRefPubMedGoogle Scholar
  36. Saha N, Datta H, Sharma PL (1990) Effects of morphine, buprenorphine, pentazocine and nalorphine on acquisition and extinction of active avoidance responses in rats. Indian J Physiol Pharmacol 34:179–182PubMedGoogle Scholar
  37. Saha N, Datta H, Sharma PL (1991) Effects of morphine on memory: interactions with naloxone, propranolol and haloperidol. Pharmacology 42:10–14CrossRefPubMedGoogle Scholar
  38. Schafe GE, Nader K, Blair HT, LeDoux JE (2001) Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective. Trends Neurosci 24:540–546CrossRefPubMedGoogle Scholar
  39. Shiigi Y, Takahashi M, Kaneto H (1990) Facilitation of memory retrieval by pretest morphine mediated by mu but not delta and kappa opioid receptors. Psychopharmacol (Berl) 102:329–332CrossRefGoogle Scholar
  40. Slipczuk L, Tomaiuolo M, Garagoli F, Weisstaub N, Katche C, Bekinschtein P, Medina JH (2013) Attenuating the persistence of fear memory storage using a single dose of antidepressant. Mol Psychiatry 18:7–8CrossRefPubMedGoogle Scholar
  41. Spain JW, Newsom GC (1991) Chronic opioids impair acquisition of both radial maze and Y-maze choice escape. Psychopharmacol (Berl) 105:101–106CrossRefGoogle Scholar
  42. Tramullas M, Martinez-Cue C, Hurle MA (2008) Chronic administration of heroin to mice produces up-regulation of brain apoptosis-related proteins and impairs spatial learning and memory. Neuropharmacology 54:640–652CrossRefPubMedGoogle Scholar
  43. Ukai M, Watanabe Y, Kameyama T (2001) Endomorphins 1 and 2, endogenous mu-opioid receptor agonists, impair passive avoidance learning in mice. Eur J Pharmacol 421:115–119CrossRefPubMedGoogle Scholar
  44. Yang C, Liu JF, Chai BS, Fang Q, Chai N, Zhao LY, Xue YX, Luo YX, Jian M, Han Y, Shi HS, Lu L, Wu P, Wang JS (2013) Stress within a restricted time window selectively affects the persistence of long-term memory. PLoS ONE 8:e59075CrossRefPubMedCentralPubMedGoogle Scholar
  45. Zarrindast MR, Rezayof A (2004) Morphine state-dependent learning: sensitization and interactions with dopamine receptors. Eur J Pharmacol 497:197–204CrossRefPubMedGoogle Scholar
  46. Zarrindast MR, Fazli-Tabaei S, Ahmadi S, Yahyavi SH (2006) Effect of lithium on morphine state-dependent memory of passive avoidance in mice. Physiol Behav 87:409–415CrossRefPubMedGoogle Scholar
  47. Zarrindast MR, Piri M, Nasehi M, Ebrahimi-Ghiri M (2012) Nitric oxide in the nucleus accumbens is involved in retrieval of inhibitory avoidance memory by nicotine. Pharmacol Biochem Behav 101:166–173CrossRefPubMedGoogle Scholar
  48. Zarrindast MR, Ardjmand A, Rezayof A, Ahmadi S (2013) The time profile of morphine effect on different phases of inhibitory avoidance memory in rat. Arch Iran Med 16:34–37PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Gerusa Paz Porto
    • 1
  • Laura Hautrive Milanesi
    • 1
  • Maribel Antonello Rubin
    • 1
    • 2
  • Carlos Fernando Mello
    • 1
    Email author
  1. 1.Graduation Program in Pharmacology, Department of Physiology and Pharmacology, Center of Health SciencesUniversidade Federal de Santa MariaSanta MariaBrazil
  2. 2.Department of Chemistry, Center of Exact and Natural SciencesUniversidade Federal de Santa MariaSanta MariaBrazil

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