Study of the effects of controlled morphine administration for treatment of anxiety, depression and cognition impairment in morphine-addicted rats

Document Type : Original Article


1 Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

2 Department of Physiology, Tehran University of Medical Sciences, International Campus, Tehran, Iran

3 Department of Surgery and Radiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran

4 Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran


Background: Morphine dependency usually results in undesired outcomes such as anxiety, depression, and cognitive alterations. In this study, morphine was used to manage morphine dependence-induced anxiety, depression, and learning and memory disturbances.
Materials and Methods: Forty rats were divided equally into five groups. Group 1 received saline for 21 days. Groups 2–5 were dependent by increasing administration of morphine (15–45 mg/kg) for 7 days. For the next 14 days, morphine was administered as the following regimen: Group 2: once daily; 45 mg/kg (positive controls), Group 3: the same dose with an increasing interval (6 h longer than the previous intervals each time), Group 4: the same dose with an irregular intervals (12, 24, 36 h intervals interchangeably), and Group 5: decreasing doses once daily (every time 2.5 mg/kg less than the former dosage). On days 22–26, elevated plus maze (EPM), open field test (OFT), forced swim test (FST), and tail suspension test (TST) were performed to investigate anxiety level and depression in animals. Between 17th and 21st days, Morris water maze (MWM) was used to evaluate the spatial learning and memory.
Results: Chronic morphine administration caused depression and anxiety as observed by FST, EPM, and TST and decreased motor activity in OFT and caused impairment in learning and memory performance in MWM. Treatment with our protocol as increasing interval, irregular interval, and decreasing dosage of morphine caused marked reduction in depression, anxiety, and improved cognition performance compared with positive control group; and attenuated motor deficits in morphine-dependent rats, remarkably.
Conclusions: Change in dosage regimens of morphine can reduce morphine-induced anxiety, depression, and cognitive impairments.


Motaghinejad M, Ebrahimzadeh A, Shabab B. Preventive effect of central administration of venlafaxine on morphine physical dependence, nociception, and blood cortisol level in rat. Int J Prev Med 2014;5:1422-31.  Back to cited text no. 1
Allan L, Hays H, Jensen NH, de Waroux BL, Bolt M, Donald R, et al. Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ 2001;322:1154-8.  Back to cited text no. 2
Motaghinejad M, Bangash MY, Hosseini P, Karimian SM, Motaghinejad O. Attenuation of morphine withdrawal syndrome by various dosages of curcumin in comparison with clonidine in mouse: Possible mechanism. Iran J Med Sci 2015;40:125-32.  Back to cited text no. 3
Swendsen JD, Merikangas KR. The comorbidity of depression and substance use disorders. Clin Psychol Rev 2000;20:173-89.  Back to cited text no. 4
Compton WM 3rd, Cottler LB, Ben Abdallah A, Phelps DL, Spitznagel EL, Horton JC. Substance dependence and other psychiatric disorders among drug dependent subjects: Race and gender correlates. Am J Addict 2000;9:113-25.  Back to cited text no. 5
Curran HV, Kleckham J, Bearn J, Strang J, Wanigaratne S. Effects of methadone on cognition, mood and craving in detoxifying opiate addicts: A dose-response study. Psychopharmacology (Berl) 2001;154:153-60.  Back to cited text no. 6
Motaghinejad M, et al. Protective effects of various dosage of curcumin against morphine induced apoptosis and oxidative stress in rat isolated hippocampus. Pharmacol Rep 2014; 67:230-5.  Back to cited text no. 7
Motaghinejad M, Ghaleni MA, Motaghinejad O. Preventive effects of forced exercise against alcohol-induced physical dependency and reduction of pain perception threshold. Int J Prev Med 2014;5:1299-307.  Back to cited text no. 8
McClung CA. The molecular mechanisms of morphine addiction. Rev Neurosci 2006;17:393-402.  Back to cited text no. 9
De Vries TJ, Shippenberg TS. Neural systems underlying opiate addiction. J Neurosci 2002;22:3321-5.  Back to cited text no. 10
Lee B, Shim I, Lee H, Yin CS, Park HK, Yang JS, et al. Morphine-induced locomotor response and Fos expression in rats are inhibited by acupuncture. Neurol Res 2010;32 Suppl 1:107-10.  Back to cited text no. 11
Contet C, Kieffer BL, Befort K. Mu opioid receptor: A gateway to drug addiction. Curr Opin Neurobiol 2004;14:370-8.  Back to cited text no. 12
Georges F, Stinus L, Le Moine C. Mapping of c-fos gene expression in the brain during morphine dependence and precipitated withdrawal, and phenotypic identification of the striatal neurons involved. Eur J Neurosci 2000;12:4475-86.  Back to cited text no. 13
Ammon-Treiber S, Höllt V. Morphine-induced changes of gene expression in the brain. Addict Biol 2005;10:81-9.  Back to cited text no. 14
Motaghinejad M, Motevalian M, Asadi-Ghalehni M, Motaghinejad O. Attenuation of morphine withdrawal signs, blood cortisol and glucose level with forced exercise in comparison with clonidine. Adv Biomed Res 2014;3:171.  Back to cited text no. 15
[PUBMED]  Medknow Journal  
Perrine SA, Sheikh IS, Nwaneshiudu CA, Schroeder JA, Unterwald EM. Withdrawal from chronic administration of cocaine decreases delta opioid receptor signaling and increases anxiety- and depression-like behaviors in the rat. Neuropharmacology 2008;54:355-64.  Back to cited text no. 16
Motaghinejad M, Karimian SM, Motaghinejad O, Shabab B, Asadighaleni M, Fatima S. The effect of various morphine weaning regimens on the sequelae of opioid tolerance involving physical dependency, anxiety and hippocampus cell neurodegeneration in rats. Fundam Clin Pharmacol 2015;29:299-309.  Back to cited text no. 17
Motaghinejad M, Sadeghi-Hashjin G, Koohi MK, Karimian SM. Attenuation of withdrawal signs, blood cortisol, and glucose level with various dosage regimens of morphine after precipitated withdrawal syndrome in mice. Iran J Med Sci 2016;41:53-8.  Back to cited text no. 18
Motaghinejad M, Karimian M, Motaghinejad O, Shabab B, Yazdani I, Fatima S. Protective effects of various dosage of Curcumin against morphine induced apoptosis and oxidative stress in rat isolated hippocampus. Pharmacol Rep 2015;67:230-5.  Back to cited text no. 19
Fox JG, Lynn C. Anderson, Franklin M. Loew and Fred W. Quimby, Laboratory Animal Medicine. Elsevier: Academic Press; 2002.  Back to cited text no. 20
Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review. Eur J Pharmacol 2003;463:3-33.  Back to cited text no. 21
Motaghinejad M, Motevalian M, Shabab B. Neuroprotective effects of various doses of topiramate against methylphenidate induced oxidative stress and inflammation in rat isolated hippocampus. Clin Exp Pharmacol Physiol 2016;43:360-71.  Back to cited text no. 22
Motaghinejad M, Motevalian M, Shabab B. Effects of chronic treatment with methylphenidate on oxidative stress and inflammation in hippocampus of adult rats. Neurosci Lett 2016;619:106-13.  Back to cited text no. 23
Motaghinejad M, Motevalian M. Involvement of AMPA/kainate and GABA A receptors in topiramate neuroprotective effects against methylphenidate abuse sequels involving oxidative stress and inflammation in rat isolated hippocampus. Eur J Pharmacol 2016 [Epub ahead of print].  Back to cited text no. 24
Noori N, Bangash MY, Motaghinejad M, Hosseini P, Noudoost B. Kefir protective effects against nicotine cessation-induced anxiety and cognition impairments in rats. Adv Biomed Res 2014;3:251.  Back to cited text no. 25
[PUBMED]  Medknow Journal  
Petit-Demouliere B, Chenu F, Bourin M. Forced swimming test in mice: A review of antidepressant activity. Psychopharmacology (Berl) 2005;177:245-55.  Back to cited text no. 26
Motaghinejad M, Motevalian M, Larijani SF, Khajehamedi Z. Protective effects of forced exercise against methylphenidate-induced anxiety, depression and cognition impairment in rat. Adv Biomed Res 2015;4:134.  Back to cited text no. 27
[PUBMED]  Medknow Journal  
Walf AA, Frye CA. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2007;2:322-8.  Back to cited text no. 28
Cryan JF, Mombereau C, Vassout A. The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev 2005;29:571-625.  Back to cited text no. 29
Motaghinejad M, Motevalian M, Ebrahimzadeh A, Larijani SF, Khajehamedi Z. Reduction of methylphenidate induced anxiety, depression and cognition impairment by various doses of venlafaxine in rat. Int J Prev Med 2015;6:52.  Back to cited text no. 30
[PUBMED]  Medknow Journal  
D'Hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev 2001;36:60-90.  Back to cited text no. 31
Patti CL, Frussa-Filho R, Silva RH, Carvalho RC, Kameda SR, Takatsu-Coleman AL, et al. Behavioral characterization of morphine effects on motor activity in mice. Pharmacol Biochem Behav 2005;81:923-7.  Back to cited text no. 32
Koek W, France CP, Javors MA. Morphine-induced motor stimulation, motor incoordination, and hypothermia in adolescent and adult mice. Psychopharmacology (Berl) 2012;219:1027-37.  Back to cited text no. 33
Hyman SE. Addiction: A disease of learning and memory. Am J Psychiatry 2005;162:1414-22.  Back to cited text no. 34
Pierce RC, Kumaresan V. The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev 2006;30:215-38.  Back to cited text no. 35
Willuhn I, Willuhn I 1, Wanat MJ, Clark JJ, Phillips PE. Dopamine signaling in the nucleus accumbens of animals self-administering drugs of abuse. Curr Top Behav Neurosci. 2010;3:29-71.  Back to cited text no. 36
Yamamoto J, Kawamata T, Niiyama Y, Omote K, Namiki A. Down-regulation of mu opioid receptor expression within distinct subpopulations of dorsal root ganglion neurons in a murine model of bone cancer pain. Neuroscience 2008;151:843-53.  Back to cited text no. 37
Valverde O, Mantamadiotis T, Torrecilla M, Ugedo L, Pineda J, Bleckmann S, et al. Modulation of anxiety-like behavior and morphine dependence in CREB-deficient mice. Neuropsychopharmacology 2004;29:1122-33.  Back to cited text no. 38
Zhang Z, Schulteis G. Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze. Pharmacol Biochem Behav 2008;89:392-403.  Back to cited text no. 39
Paterson NE, Markou A. Animal models and treatments for addiction and depression co-morbidity. Neurotox Res 2007;11:1-32.  Back to cited text no. 40
Goeldner C, Lutz PE, Darcq E, Halter T, Clesse D, Ouagazzal AM, et al. Impaired emotional-like behavior and serotonergic function during protracted abstinence from chronic morphine. Biol Psychiatry 2011;69:236-44.  Back to cited text no. 41
Zarrindast MR, Rostami P, Zarei M, Roohbakhsh A. Intracerebroventricular effects of histaminergic agents on morphine-induced anxiolysis in the elevated plus-maze in rats. Basic Clin Pharmacol Toxicol 2005;97:276-81.  Back to cited text no. 42
Cadet JL, Krasnova IN. Molecular bases of methamphetamine-induced neurodegeneration. Int Rev Neurobiol 2009;88:101-19.  Back to cited text no. 43
Buckman SG, Hodgson SR, Hofford RS, Eitan S. Increased elevated plus maze open-arm time in mice during spontaneous morphine withdrawal. Behav Brain Res 2009;197:454-6.  Back to cited text no. 44
Cherny N, Ripamonti C, Pereira J, Davis C, Fallon M, McQuay H, et al. Strategies to manage the adverse effects of oral morphine: An evidence-based report. J Clin Oncol 2001;19:2542-54.  Back to cited text no. 45
Patti CL, Kameda SR, Carvalho RC, Takatsu-Coleman AL, Lopez GB, Niigaki ST, et al. Effects of morphine on the plus-maze discriminative avoidance task: Role of state-dependent learning. Psychopharmacology (Berl) 2006;184:1-12.  Back to cited text no. 46
O'Neill WM, Hanks GW, Simpson P, Fallon MT, Jenkins E, Wesnes K. The cognitive and psychomotor effects of morphine in healthy subjects: A randomized controlled trial of repeated (four) oral doses of dextropropoxyphene, morphine, lorazepam and placebo. Pain 2000;85:209-15.  Back to cited text no. 47
Ersche KD, Clark L, London M, Robbins TW, Sahakian BJ. Profile of executive and memory function associated with amphetamine and opiate dependence. Neuropsychopharmacology 2006;31:1036-47.  Back to cited text no. 48
Gruber SA, Silveri MM, Yurgelun-Todd DA. Neuropsychological consequences of opiate use. Neuropsychol Rev 2007;17:299-315.  Back to cited text no. 49
Muller DL, Unterwald EM. D1 dopamine receptors modulate deltaFosB induction in rat striatum after intermittent morphine administration. J Pharmacol Exp Ther 2005;314:148-54.  Back to cited text no. 50
Nestler EJ. Review. Transcriptional mechanisms of addiction: Role of DeltaFosB. Philos Trans R Soc Lond B Biol Sci 2008;363:3245-55.  Back to cited text no. 51
Nestler EJ. Molecular neurobiology of addiction. Am J Addict 2001;10:201-17.  Back to cited text no. 52
Bierczynska-Krzysik A, Bonar E, Drabik A, Noga M, Suder P, Dylag T, et al. Rat brain proteome in morphine dependence. Neurochem Int 2006;49:401-6.  Back to cited text no. 53
Robison AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci 2011;12:623-37.  Back to cited text no. 54
Seyedi SY, Salehi F, Payandemehr B, Hossein S, Hosseini-Zare MS, Nassireslami E, et al. Dual effect of cAMP agonist on ameliorative function of PKA inhibitor in morphine-dependent mice. Fundam Clin Pharmacol 2014;28:445-54.  Back to cited text no. 55
Nestler EJ. Molecular mechanisms of drug addiction. Neuropharmacology 2004;47 Suppl 1:24-32.  Back to cited text no. 56