A study of the neurotoxic effects of tramadol and cannabis in adolescent male albino rats

Authors

  • Ola E. Nafea Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Zagazig University, Zagazig, Sharkia, Egypt
  • Iman A. ElKhishin Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Zagazig University, Zagazig, Sharkia, Egypt
  • Othman A. Awad Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Zagazig University, Zagazig, Sharkia, Egypt
  • Dalia A. Mohamed Department of Histology and Cell Biology, Faculty of Medicine, Zagazig University, Zagazig, Sharkia, Egypt

DOI:

https://doi.org/10.18203/issn.2454-2156.IntJSciRep20162164

Keywords:

Adolescence, Opioid, Cannabinoid, Neurotoxicity, Sucrose preference, Morris water maze

Abstract

Background: Adolescence is a critical period for cerebral development. Exposure to addictive substances during this phase leads to various alterations in brain functions that persist into adulthood. The present study was designed to study the neurotoxic effects of tramadol and cannabis, alone and in combination, in adolescent male albino rats by studying their behavioral, biochemical, and histopathological neurotoxic effects and their long–term consequences after withdrawal.

Methods: For this purpose, 132 adolescent male albino rats were divided into 5 groups (22 rats/ group). Group I (negative control), received only regular diet and tap water to measure the basic parameters, Group II (positive control; IIA&IIB); IIA, gavaged with normal saline. IIB, gavaged with olive oil. Group III (tramadol), gavaged with tramadol (42, 84 and 168 mg/kg/day) in the first, second and third ten days of the study respectively. Group IV (cannabis), gavaged with hashish extract (92, 184 and 368 mg/kg/day) in the first, second and third ten days of the study respectively. Group V (tramadol+cannabis), gavaged with tramadol and hashish extract in the same doses as Group III&IV. By the end of the first month, the half number of rats was subjected to performing behavior tests. Specimens from the brain were taken for performing biochemical and histopathological studies. All remaining rats were held for another 4 weeks non–dosing spontaneous recovery period after withdrawal of the treatment and were evaluated again by the same previous parameters.

Results: Abuse of tramadol or cannabis, alone and in combination, caused antidepressant effect (sucrose preference test), impaired spatial memory (Morris water maze), elevated serotonin levels in the cerebral cortex and hippocampus, induced oxidative stress (significantly elevated malondialdehyde level and reduced catalase activity) as well as deleteriously altered brain histopathology and marked increase in brain Caspase–3 expression. However, abuse of both tramadol and cannabis conferred more antidepressant effect but more neurotoxic effect. After withdrawal, the antidepressant effect was reversed, no improvement of the spatial memory, marked depletion of 5–HT, more improvement in antioxidants and apoptotic markers and incomplete regression of brain histopathological alteration resulted.

Conclusions: Abuse of tramadol and cannabis, alone and in combination, induced neurotoxicity which proved behaviorally, biochemically and histopathologically.

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References

Gipson DC, Kalivas WP. Neural Basis of Drug Addiction. In: De Micheli D, Andrade MAL, da Silva AE, de Souza Formigoni OML, eds. Drug Abuse in Adolescence: Neurobiological, Cognitive, and Psychological Issues. Switzerland: Cham: Springer International Publishing; 2016:37–56.

Cadet JL, Bisagno V, Milroy CM. Neuropathology of substance use disorders. Acta Neuropathol. 2014;127(1):91–107.

Cunha–Oliveira T, Rego AC, Oliveira CR. Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs. Brain Res Rev. 2008;58(1):192–208.

Cunha–Oliveira T, Rego AC, Garrido J, Borges F, Macedo T, Oliveira CR. Neurotoxicity of heroin–cocaine combinations in rat cortical neurons. Toxicol. 2010;276(1):11–7.

Rubino T, Vigano D, Realini N, Guidali C, Braida D, Capurro V, et al. Chronic delta9–tetrahydrocannabinol during adolescence provokes sex–dependent changes in the emotional profile in adult rats: behavioral and biochemical correlates. Neuropsychopharmacol. 2008;33(11):2760–71.

Omotoso GO, Adekeye MO, Ariyo AA, Ibitolu JO, Oyeyemi OA, Enaibe BU. Neurohistochemical studies of adolescent rats’ prefrontal cortex exposed to prenatal nicotine. Ibnosina J Med Biomed Sci. 2014;6(1):25–30.

Jacobus J, Tapert SF. Neurotoxic effects of alcohol in adolescence. Ann Rev Clin Psychol. 2013;9; 703–721.

Batta A. TRAMADOL–A drug to be used cautiously. Int J Curr Res Med Sci. 2016;2(2):11–7.

Abdel–Hamid IA, Andersson K–E, Waldinger MD, Anis TH. Tramadol abuse and sexual function. Sex Med Rev. 2016;4(3):235-46.

Taghaddosinejad F, Mehrpour O, Afshari R, Seghatoleslami A, Abdollahi M, Dart RC. Factors related to seizure in tramadol poisoning and its blood concentration. J Med Toxicol. 2011;7(3):183–8.

Karrari P, Mehrpour O, Balali–Mood M. Iranian crystal: a misunderstanding of the crystal–meth. J Res Med Sci. 2012;17(2),203–4.

Kusari S, Tatsimo SJ, Zühlke S, Spiteller M. Synthetic origin of tramadol in the environment. Angew Chem Int Ed Engl. 2016;55(1):240–3.

Bourne PG. Marijuana: Medical Applications, Recreational Use and Substance Abuse Disorders. In: Friedman, H.S. ed. Encyclopedia of Mental Health. 2nd ed. Waltham, Massachusetts: Academic Press; 2016:39–45.

Camchong J, Lim KO, Kumra S. Adverse effects of cannabis on adolescent brain development: A longitudinal study. Cerebral Cortex. 2016: doi: 10.1093/cercor/bhw015.

Hill S, Thomas SH. Recreational drug toxicity. Clin Med. 2008;8(1):99–103.

Fratta W, Fattore L. Molecular mechanisms of cannabinoid addiction. Curr Opin Neurobiol. 2013;23(4):487–92.

Reece AS. Chronic toxicology of cannabis. Clin Toxicol. 2009;47(6):517–24.

Niesink RJ, van Laar MW. Does cannabidiol protect against adverse psychological effects of THC? Front Psychiarty. 2013;4:130.

Murillo–Rodríguez E, Sarro–Ramírez A, Sánchez D, Mijangos–Moreno S, Tejeda–Padrón A, Poot–Aké A, et al. Potential Effects of Cannabidiol as a Wake–Promoting Agent. Curr Neuropharmacol. 2014;12(3):269–72.

Scherma M, Dessì C, Muntoni AL, Lecca S, Satta V, Luchicchi A, et al. Adolescent Δ9–Tetrahydrocannabinol Exposure Alters WIN55, 212–2 Self–Administration in Adult Rats. Neuropsychopharmacol. 2016;41(5):1416–26.

Marie D, Fergusson DM, Boden JM. Links between ethnic identification, cannabis use and dependence, and life outcomes in a New Zealand birth cohort. Aust N Z J Psychiatry. 2008;42(9):780–8.

Yassa HA, Abd El Wahab AD, Shehata MM, Abdel–Hady RH, Abdel–Aal KM. Subchronic toxicity of cannabis leaves on male albino rats. Hum Experimental Toxicol. 2009; 29(1):37–47.

Miras C, Kephalas T, Papadakis D. The effect of hashish extract on the norepinephrine in rabbit brain. Bull Narcot. 1971;23:33–4.

Laviola G, Macrı̀ S, Morley–Fletcher S, Adriani W. Risk–taking behavior in adolescent mice: psychobiological determinants and early epigenetic influence. Neurosci Biobehav Rev. 2003;27(1):19–31.

Quinn HR, Matsumoto I, Callaghan PD, Long LE, Arnold JC, Gunasekaran N, et al. Adolescent rats find repeated Δ9–THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure. Neuropsychopharmacol. 2008;33(5):1113–26.

Marco EM, Adriani W, Ruocco LA, Canese R, Sadile AG, Laviola G. Neurobehavioral adaptations to methylphenidate: The issue of early adolescent exposure. Neurosci Biobehav Rev. 2011;35(8):1722–39.

Borgerding MP, Absher RK, So T–Y. Tramadol use in pediatric sickle cell disease patients with vaso–occlusive crisis. World J Clin Pediatr. 2013;2(4): 65–9.

Reagan–Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22(3):659–61.

Atici S, Cinel L, Cinel I, Doruk N, Aktekin M, Akca A, et al. Opioid neurotoxicity: comparison of morphine and tramadol in an experimental rat model. Int J Neurosci. 2004;114(8):1001–11.

Osman AM, Shaalan M, Wagih I, Afifi M. Anticonvulsant effects of hashish in human epileptics. Egypt J Psychiatry. 1984;7:85–97.

Rubio P, De Fonseca FRg, Martı́n–Calderón JL, Del Arco I, Bartolomé S, Villanúa MaA, et al. Maternal exposure to low doses of Δ9–tetrahydrocannabinol facilitates morphine–induced place conditioning in adult male offspring. Pharmacol Biochem Behav. 1998;61(3):229–38.

Hong S, Flashner B, Chiu M, ver Hoeve E, Luz S, Bhatnagar S. Social isolation in adolescence alters behaviors in the forced swim and sucrose preference tests in female but not in male rats. Physiol Behav. 2012;105(2):269–75.

Monteggia LM, Luikart B, Barrot M, Theobold D, Malkovska I, Nef S, et al. Brain–derived neurotrophic factor conditional knockouts show gender differences in depression–related behaviour. Biol Psychiatry. 2007;61(2):187–97.

Morris R. Developments of a water–maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984;11(1):47–60.

West MJ. Regionally specific loss of neurons in the aging human hippocampus. Neurobiol Aging. 1993;14(4):287–93.

Hadad–Ophir O, Albrecht A, Stork O, Richter–Levin G. Amygdala activation and GABAergic gene expression in hippocampal sub–regions at the interplay of stress and spatial learning. Front Behav Neurosci. 2014;8:3.

Baraka A, ElGhotny S. Study of the effect of inhibiting galanin in Alzheimer's disease induced in rats. Eur J Pharmacol. 2010;641(2):123–7.

Spijker S. Dissection of rodent brain regions. Neuroproteomics. 2011;57:13–26.

Cox BM, Shah MM, Cichon T, Tancer ME, Galloway MP, Thomas DM, et al. Behavioral and neurochemical effects of repeated MDMA administration during late adolescence in the rat. Prog Neuro–Psychopharmacol Biol Psychiatry. 2014;48:229–35.

Krajewska M, Wang H–G, Krajewski S, Zapata JM, Shabaik A, Gascoyne R, et al. Immunohistochemical analysis of in vivo patterns of expression of CPP32 (Caspase–3), a cell death protease. Cancer Res. 1997;57(8):1605–13.

Mustafa HN, El Awdan SA, Hegazy GA, Jaleel GAA. Prophylactic role of coenzyme Q10 and Cynara scolymus L on doxorubicin–induced toxicity in rats: Biochemical and immunohistochemical study. Indian J Pharmacol. 2015;47(6):649.

Squeglia LM, Jacobus J, Tapert SF. The influence of substance use on adolescent brain development. Clin EEG Neurosci. 2009;40(1):31–8.

Ozerov A, Bagmetova V, Chernysheva YV, Tyurenkov I. Comparison of the efficiency of adeprophen and antidepressants of various groups on the model of reserpine–induced depression in rats. Bull Exp Biol Med. 2016;160(5):649–52.

Arango V, Underwood MD, Mann JJ. Serotonin brain circuits involved in major depression and suicide. Prog Brain Res. 2002;136:443–53.

Darwish IE, Maklad HM, Diab IH. Behavioral and neuronal biochemical possible effects in experimental induced chronic mild stress in male albino rats under the effect of oral barley administration in comparison to venlafaxine. Int J Physiol Pathophysiol Pharmacol. 2013;5(2):128.

Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879–923.

Vazzana M, Andreani T, Fangueiro J, Faggio C, Silva C, Santini A, et al. Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co–administration of drugs and new drug delivery systems. Biomed Pharmacother. 2015;70:234–8.

Abdel–Salam OM, Salem NA, El–Shamarka ME–S, Ahmed NA–S, Hussein JS, El–Khyat ZA. Cannabis–induced impairment of learning and memory: Effect of different nootropic drugs. EXCLI J. 2013;12:193.

Szkutnik–Fiedler D, Kus K, Balcerkiewicz M, Grześkowiak E, Nowakowska E, Burda K, et al. Concomitant use of tramadol and venlafaxine–evaluation of antidepressant–like activity and other behavioral effects in rats. Pharmacol Rep. 2012;64(6):1350–8.

Senay EC, Adams EH, Geller A, Inciardi JA, Munoz A, Schnoll SH, et al. Physical dependence on Ultram®(tramadol hydrochloride): both opioid–like and atypical withdrawal symptoms occur. Drug Alcohol Depend. 2003;69(3):233–41.

Haney M. The marijuana withdrawal syndrome: diagnosis and treatment. Curr Psychiatry Rep. 2005;7(5):360–6.

Polydoro M, Schroder N, Lima MN, Caldana F, Laranja DC, Bromberg E, et al. Haloperidol– and clozapine–induced oxidative stress in the rat brain. Pharmacol Biochem Behav. 2004;78(4):751–6.

Schroder N, de Lima MN, Quevedo J, Dal Pizzol F, Roesler R. Impairing effects of chronic haloperidol and clozapine treatment on recognition memory: possible relation to oxidative stress. Schizophrenia Res. 2005;73(3):377–8.

Clausen A, Doctrow S, Baudry M. Prevention of cognitive deficits and brain oxidative stress with superoxide dismutase/catalase mimetics in aged mice. Neurobiol Aging. 2010;31(3):425–33.

Hosseini–Sharifabad A, Rabbani M, Sharifzadeh M, Bagheri N. Acute and chronic tramadol administration impair spatial memory in rat. Res Pharm Sci. 2016;11(1):49–57.

Lubman DI, Cheetham A, Yucel M. Cannabis and adolescent brain development. Pharmacol Ther. 2015;148:1–16.

Lehmann O, Bertrand F, Jeltsch H, Morer M, Lazarus C, Will B, et al. 5,7–DHT–induced hippocampal 5–HT depletion attenuates behavioural deficits produced by 192 IgG–saporin lesions of septal cholinergic neurons in the rat. Eur J Neurosci. 2002;15(12):1991–2006.

Majlessi N, Kadkhodaee M, Parviz M, Naghdi N. Serotonin depletion in rat hippocampus attenuates L–NAME–induced spatial learning deficits. Brain Res. 2003;963(2):244–51.

Adams W, Kusljic S, van den Buuse M. Serotonin depletion in the dorsal and ventral hippocampus: effects on locomotor hyperactivity, prepulse inhibition and learning and memory. Neuropharmacol. 2008;55(6):1048–55.

Normile HJ, Jenden DJ, Kuhn DM, Wolf WA, Altman HJ. Effects of combined serotonin depletion and lesions of the nucleus basalis magnocellularis on acquisition of a complex spatial discrimination task in the rat. Brain Res. 1990;536(1):245–50.

Sarikaya S, Gulcin I. Radical scavenging and antioxidant capacity of serotonin. Curr Bioact Comp. 2013;9(2):143–52.

Jackson R, McNeil B, Taylor C, Holl G, Ruff D, Gwebu E. Effect of aged garlic extract on Caspase–3 activity, in vitro. Nutr Neurosci. 2002;5(4):287–90.

Schwerk C, Schulze–Osthoff K. Non–apoptotic functions of caspases in cellular proliferation and differentiation. Biochem Pharmacol. 2003;66(8):1453–8.

Ghoneim FM, Khalaf HA, Elsamanoudy AZ, Helaly AN. Effect of chronic usage of tramadol on motor cerebral cortex and testicular tissues of adult male albino rats and the effect of its withdrawal: Histological, immunohistochemical and biochemical study. Int J Clinical Exp Pathol. 2014;7(11):7323–41.

Maschke M, Fehlings T, Kastrup O, Wilhelm HW, Leonhardt G. Toxic leukoencephalopathy after intravenous consumption of heroin and cocaine with unexpected clinical recovery. J Neurol. 1999;246(9):850–1.

Iversen L. Cannabis and the brain. Brain. 2003;126(6):1252–70.

Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid–opioid interaction in chronic pain. Clin Pharmacol Ther. 2011;90(6):844–51.

Bartsch AJ, Homola G, Biller A, Smith SM, Weijers HG, Wiesbeck GA, et al. Manifestations of early brain recovery associated with abstinence from alcoholism. Brain. 2007;130(1):36–47.

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Published

2016-07-04

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Original Research Articles