Does Tramadol Exposure Have Unfavorable Effects on Hippocampus? A Review Study

Document Type : Review Article(s)

Authors

1 Department of Anatomical Sciences, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran

2 Department of Anatomical Sciences, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran

3 Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran

4 1.Department of Anatomical Sciences, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran 2.Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran

10.34172/ahj.1481

Abstract

Background: Tramadol, one of the most common opioid pain relievers, acts upon the µ-receptor in the central nervous system (CNS) 
to alleviate pain associated with various situations like postoperative pain, arthritis, and muscular pain. Additionally, it has been 
utilized to address depression and anxiety disorders. Extensive research has shown that tramadol can potentially inflict irreversible 
harm on different regions of the CNS, including the cerebrum, cerebellum, amygdala, and, notably, the hippocampal formation. 
However, the precise mechanism behind these effects remains unclear. Within this study, we conducted a comprehensive 
examination of the impacts of tramadol on the CNS, specifically focusing on hippocampal formation. 
Methods: In this study, we collected relevant articles published between 2000 and 2022 by conducting searches using specific 
keywords, including tramadol, tramadol hydrochloride, central nervous system, hippocampus, and hippocampal formation, in 
various databases.
Findings: The results of this study proposed several processes by which tramadol may impact the CNS, including the induction of 
apoptosis, autophagy, excessive production of free radicals, and dysfunction of cellular organelles. These processes ultimately lead 
to disturbances in neural cell function, particularly within the hippocampus. Furthermore, it is revealed that tramadol administration 
led to a significant decrease in the neural cell count and the volume of various regions within the brain and spinal cord.
Conclusion: Consequently, neuropsychological impairments, such as memory formation, attention deficits, and cognitive 
impairment, may happen. This finding highlights the potential impacts of tramadol on neural structures and warrants further 
investigation.

Highlights

Samira Ezi: (Google Scholar) (PubMed)

Mehri Shadi: (Google Scholar) (PubMed)

Masood Vafaei-Nezhad: (Google Scholar) (PubMed)

Saeed Vafaei-Nezhad: (Google Scholar) (PubMed)

Keywords


1. Valipour R, Shekari A, Setareh M. Identification of medicine 
components in herbal drugs for addiction treatment; a case 
study of Zanjan city. Iran J Forensic Med. 2019;25(1):61-4.
2. Aghajanpour F, Eskandarian Boroujeni M, Jahanian A, Soltani 
R, Ezi S, Khatmi A, et al. Tramadol: a potential neurotoxic 
agent affecting prefrontal cortices in adult male rats and PC12 cell line. Neurotox Res. 2020;38(2):385-97. doi: 10.1007/
s12640-020-00214-z.
3. Ezi S, Eskandarian Boroujeni M, Khatmi A, Vakili K, Fathi M, 
Abdollahifar MA, et al. Chronic exposure to tramadol induces 
neurodegeneration in the cerebellum of adult male rats. 
Neurotox Res. 2021;39(4):1134-47. doi: 10.1007/s12640-
021-00354-w.
4. Subedi M, Bajaj S, Kumar MS, Yc M. An overview of tramadol 
and its usage in pain management and future perspective. 
Biomed Pharmacother. 2019;111:443-51. doi: 10.1016/j.
biopha.2018.12.085.
5. Khatmi A, Eskandarian Boroujeni M, Ezi S, Mirbehbahani 
SH, Aghajanpour F, Soltani R, et al. Combined molecular, 
structural and memory data unravel the destructive effect of 
tramadol on hippocampus. Neurosci Lett. 2022;771:136418. 
doi: 10.1016/j.neulet.2021.136418.
6. 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. doi: 10.1016/j.biopha.2015.01.022.
7. Lavasani H, Sheikholeslami B, Hosseinzadeh Ardakani 
Y, Abdollahi M, Hakemi L, Rouini MR. Study of the 
pharmacokinetic changes of tramadol in diabetic rats. Daru. 
2013;21(1):17. doi: 10.1186/2008-2231-21-17 .
8. Eassa BI, El-Shazly MA. Safety and efficacy of tramadol 
hydrochloride on treatment of premature ejaculation. Asian J 
Androl. 2013;15(1):138-42. doi: 10.1038/aja.2012.96.
9. Ali OK, Ahmed AJ, Mawlood AG. Effects of tramadol on 
histopathological and biochemical parameters in male rabbits. 
Am J Biol Life Sci. 2015;3(3):85-90.
10. Edinoff AN, Kaplan LA, Khan S, Petersen M, Sauce E, 
Causey CD, et al. Full Opioid Agonists and Tramadol: 
Pharmacological and Clinical Considerations. Anesth Pain 
Med 2021;11(4):e119156. doi: 10.5812/aapm.119156.
11. Lee SH, Cho SY, Lee HG, Choi JI, Yoon MH, Kim WM. 
Tramadol induced paradoxical hyperalgesia. Pain Physician. 
2013;16(1):41-4.
12. Callaghan CK, Rouine J, O’Mara SM. Potential roles for 
opioid receptors in motivation and major depressive 
disorder. Prog Brain Res. 2018;239:89-119. doi: 10.1016/
bs.pbr.2018.07.009.
13. Hussein OA, Abdel Mola AF, Rateb A. Tramadol administration 
induced hippocampal cells apoptosis, astrogliosis, and 
microgliosis in juvenile and adult male mice, histological 
and immunohistochemical study. Ultrastruct Pathol. 
2020;44(1):81-102. doi: 10.1080/01913123.2019.1711480.
14. Abdel-Hamid IA, Andersson KE, Waldinger MD, Anis 
TH. Tramadol abuse and sexual function. Sex Med Rev. 
2016;4(3):235-46. doi: 10.1016/j.sxmr.2015.10.014.
15. Nafea OE, ElKhishin IA, Awad OA, Mohamed DA. A study of 
the neurotoxic effects of tramadol and cannabis in adolescent 
male albino rats. Int J Sci Rep. 2016;2(7):143-54. doi: 
10.18203/issn.2454-2156.IntJSciRep20162164.
16. Ahmed AI, El-Dawy K, Fawzy MM, Abdallah HA, Elsaid HN, 
Elmesslamy WO. Retrospective review of tramadol abuse. 
Slov Vet Res. 2018;55(Suppl 20):471-83. doi: 10.26873/svr677-2018.
17. Zebedee LU, Bariweni MW, Oboma YI, Ilegbedion IG. 
Tramadol abuse and addiction: effects on learning, memory, 
and organ damage. Egypt Pharm J. 2022;21(1):75-83.
18. Soltani R, Eskandarian Boroujeni M, Aghajanpour F, Khatmi A, 
Ezi S, Mirbehbahani SH, et al. Tramadol exposure upregulated 
apoptosis, inflammation and autophagy in PC12 cells and rat’s 
striatum: an in vitro- in vivo approach. J Chem Neuroanat. 
2020;109:101820. doi: 10.1016/j.jchemneu.2020.101820.
19. Stoops WW, Lofwall MR, Nuzzo PA, Craig LB, Siegel AJ, 
Walsh SL. Pharmacodynamic profile of tramadol in humans: 
influence of naltrexone pretreatment. Psychopharmacology 
(Berl). 2012;223(4):427-38. doi: 10.1007/s00213-012-2739-4.
20. Nakhaee S, Hoyte C, Dart RC, Askari M, Lamarine RJ, 
Mehrpour O. A review on tramadol toxicity: mechanism of 
action, clinical presentation, and treatment. Forensic Toxicol. 
2021;39(2):293-310. doi: 10.1007/s11419-020-00569-0 .
21. Omar NM. Nigella sativa oil alleviates ultrastructural 
alterations induced by tramadol in rat motor cerebral cortex. 
J Microsc Ultrastruct. 2016;4(2):76-84. doi: 10.1016/j.
jmau.2015.12.001.
22. Imanpour V, Reisi P. The effect of orexin-2 and 
endocannabinoid-1 antagonists on neuronal activity of 
hippocampal CA1 pyramidal neurons in response to tramadol 
in rats. Adv Biomed Res. 2022;11:26. doi: 10.4103/abr.
abr_65_21.
23. Rahimi HR, Soltaninejad K, Shadnia S. Acute tramadol 
poisoning and its clinical and laboratory findings. J Res Med 
Sci. 2014;19(9):855-9.
24. Dhagudu NK, Erravalli A, Sarkar S, Chadda RK. Tramadolrelated adverse drug reactions at an addiction psychiatry 
setting: a cross-sectional analysis. Indian J Psychol Med. 
2019;41(6):593-5. doi: 10.4103/ijpsym.ijpsym_330_18.
25. Mohammadnejad L, Soltaninejad K. Tramadol-induced organ 
toxicity via oxidative stress: a review study. Int J Med Toxicol 
Forensic Med. 2022;12(1):35430. doi: 10.32598/ijmtfm.
v12i1.35430.
26. Elkhateeb A, El Khishin I, Megahed O, Mazen F. Effect of 
Nigella sativa Linn oil on tramadol-induced hepato- and 
nephrotoxicity in adult male albino rats. Toxicol Rep. 
2015;2:512-9. doi: 10.1016/j.toxrep.2015.03.002.
27. Lagard C, Chevillard L, Malissin I, Risède P, Callebert J, Labat 
L, et al. Mechanisms of tramadol-related neurotoxicity in the 
rat: does diazepam/tramadol combination play a worsening 
role in overdose? Toxicol Appl Pharmacol. 2016;310:108-19. 
doi: 10.1016/j.taap.2016.09.013.
28. 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. doi: 10.1007/s13181-011-0168-0.
29. Kose EA, Bakar B, Ayva SK, Kilinc K, Apan A. Effects of 
intracisternal tramadol on cerebral and spinal neuronal cells 
in rat. Minerva Anestesiol. 2014;80(8):904-12.
30. Ragab IK, Mohamed HZ. Histological changes of the adult 
albino rats entorhinal cortex under the effect of tramadol 
administration: histological and morphometric study. Alex J 
Med. 2017;53(2):123-33. doi: 10.1016/j.ajme.2016.05.001.
31. 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. doi: 10.1080/00207450490461314.
32. Fathy H, Yassa H, Almaz D, Mohamed R. Acute and subchronic 
tramadol toxicity on brain and spinal cord of male albino rats. 
Ain Shams J Forensic Med Clin Toxicol. 2013;20(1):135-45. 
doi: 10.21608/ajfm.2013.19397.
33. Cherner M, Suarez P, Casey C, Deiss R, Letendre S, Marcotte 
T, et al. Methamphetamine use parameters do not predict 
neuropsychological impairment in currently abstinent 
dependent adults. Drug Alcohol Depend. 2010;106(2-3):154-
63. doi: 10.1016/j.drugalcdep.2009.08.010.
34. Zakaryaee H, Mollazadeh J, Aflakseir A, Khormaei F, Soofi 
A. Cognitive impairment in methamphetamine buprenorphin 
and tramadol users. Eur J Sci Res. 2012;68(3):321-7.
35. Niknamfar S, Nouri Zadeh-Tehrani S, Sadat-Shirazi MS, 
Akbarabadi A, Rahimi-Movaghar A, Zarrindast MR. μ-Opioid 
receptor in the CA1 involves in tramadol and morphine cross 
state-dependent memory. Neurosci Lett. 2019;705:177-82. 
doi: 10.1016/j.neulet.2019.04.054.
36. Song D, Wang D, Yang Q, Yan T, Wang Z, Yan Y, et al. The 
lateralization of left hippocampal CA3 during the retrieval of 
spatial working memory. Nat Commun. 2020;11(1):2901. 
doi: 10.1038/s41467-020-16698-4.
37. Umbach G, Kantak P, Jacobs J, Kahana M, Pfeiffer BE, Sperling 
M, et al. Time cells in the human hippocampus and entorhinal 
cortex support episodic memory. Proc Natl Acad Sci U S A. 
2020;117(45):28463-74. doi: 10.1073/pnas.2013250117.
38. Vafaei-Nezhad S, Hami J, Sadeghi A, Ghaemi K, Hosseini M, 
Abedini MR, et al. The impacts of diabetes in pregnancy on 
hippocampal synaptogenesis in rat neonates. Neuroscience. 
2016;318:122-33. doi: 10.1016/j.neuroscience.2016.01.025.
39. Vafaei-Nezhad S, Vafaei-Nezhad M, Shadi M, Ezi S. The 
impact of diabetes on hippocampus. In: Zhang X, ed.Hippocampus-Cytoarchitecture and Diseases. IntechOpen; 
2021. doi: 10.5772/intechopen.99895.
40. Hami J, Shojae F, Vafaee-Nezhad S, Lotfi N, Kheradmand H, 
Haghir H. Some of the experimental and clinical aspects of the 
effects of the maternal diabetes on developing hippocampus. 
World J Diabetes. 2015;6(3):412-22. doi: 10.4239/wjd.
v6.i3.412.
41. Alam MJ, Kitamura T, Saitoh Y, Ohkawa N, Kondo T, Inokuchi 
K. Adult neurogenesis conserves hippocampal memory 
capacity. J Neurosci. 2018;38(31):6854-63. doi: 10.1523/
jneurosci.2976-17.2018.
42. Khalifa HE, Darweesh A, Hassaan S, Mostafa S. Assessment 
of cognitive functions in tramadol-dependent patients. 
Middle East Curr Psychiatr. 2018;25(1):2-5. doi: 10.1097/01.
xme.0000526928.54570.
43. Szkutnik-Fiedler D, Kus K, Ratajczak P, Antoniów M, 
Nowakowska E, Grześkowiak E. Coadministration of tramadol 
with aripiprazole and venlafaxine--the effect on spatial memory 
functions in male rats. Pharmacol Rep. 2016;68(2):451-6. doi: 
10.1016/j.pharep.2015.11.003.
44. Bassiony MM, Youssef UM, Hassan MS, Salah El-Deen GM, 
El-Gohari H, Abdelghani M, et al. Cognitive impairment 
and tramadol dependence. J Clin Psychopharmacol. 
2017;37(1):61-6. doi: 10.1097/jcp.0000000000000617.
45. Hassaan SH, Khalifa H, Darwish AM. Effects of extended 
abstinence on cognitive functions in tramadol-dependent 
patients: a cohort study. Neuropsychopharmacol Rep. 
2021;41(3):371-8. doi: 10.1002/npr2.12188.
46. Mahdi S. Attention and memory in tramadol addiction. Sohag 
Med J. 2018;22(3):285-9. doi: 10.21608/smj.2018.34496.
47. Elrassas HH, Elsayed YA, El Nagar ZM, Abdeen MS, 
Mohamed AT. Cognitive impairment in patients diagnosed 
with tramadol dependence compared to healthy controls. 
Int Clin Psychopharmacol. 2021;36(1):38-44. doi: 10.1097/
yic.0000000000000340.
48. Ahmadi M, Hoseinzade A, Haghighi S, Yosefi S. Complex 
partial seizure and hippocampus atrophy caused by 
tramadol abuse: a case study. Ann Mil Health Sci Res. 
2017;15(1):e61240. doi: 10.5812/amh.61240.
49. Jafari-Sabet M, Jafari-Sabet AR, Dizaji-Ghadim A. Tramadol 
state-dependent memory: involvement of dorsal hippocampal 
muscarinic acetylcholine receptors. Behav Pharmacol. 
2016;27(5):470-8. doi: 10.1097/fbp.0000000000000239.
50. Sardari M, Rezayof A, Khodagholi F, Zarrindast MR. Basolateral 
amygdala GABA-A receptors mediate stress-induced memory 
retrieval impairment in rats. Int J Neuropsychopharmacol. 
2014;17(4):603-12. doi: 10.1017/s1461145713001363.
51. 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.
52. Vago DR, Bevan A, Kesner RP. The role of the direct perforant 
path input to the CA1 subregion of the dorsal hippocampus 
in memory retention and retrieval. Hippocampus. 
2007;17(10):977-87. doi: 10.1002/hipo.20329.
53. Topolnik L, Tamboli S. The role of inhibitory circuits in 
hippocampal memory processing. Nat Rev Neurosci. 
2022;23(8):476-92. doi: 10.1038/s41583-022-00599-0.
54. Elwy A, Tabl G. Impact of tramadol and morphine abuse on 
the activities of acetylcholine esterase, Na+/K+-ATPase and 
related parameters in cerebral cortices of male adult rats. 
Electron Physician. 2017;9(3):4027-34. doi: 10.19082/4027.
55. Christie MJ. Cellular neuroadaptations to chronic opioids: 
tolerance, withdrawal and addiction. Br J Pharmacol. 
2008;154(2):384-96. doi: 10.1038/bjp.2008.100.
56. Matthies H, Schroeder H, Becker A, Loh H, Höllt V, Krug M. 
Lack of expression of long-term potentiation in the dentate 
gyrus but not in the CA1 region of the hippocampus of 
mu-opioid receptor-deficient mice. Neuropharmacology. 
2000;39(6):952-60. doi: 10.1016/s0028-3908(99)00203-8.
57. Korpi ER, den Hollander B, Farooq U, Vashchinkina E, 
Rajkumar R, Nutt DJ, et al. Mechanisms of action and 
persistent neuroplasticity by drugs of abuse. Pharmacol Rev. 
2015;67(4):872-1004. doi: 10.1124/pr.115.010967.
58. Sivakumar S, Ghasemi M, Schachter SC. Targeting NMDA 
receptor complex in management of epilepsy. Pharmaceuticals 
(Basel). 2022;15(10):1297. doi: 10.3390/ph15101297.
59. Weiss F, Caruso V, De Rosa U, Beatino MF, Barbuti M, 
Nicoletti F, et al. The role of NMDA receptors in bipolar 
disorder: a systematic review. Bipolar Disord. 2023;25(8):624-
36. doi: 10.1111/bdi.13335.
60. Jafari-Sabet M, Mofidi H, Attarian-Khosroshahi MS. NMDA 
receptors in the dorsal hippocampal area are involved in 
tramadol state-dependent memory of passive avoidance 
learning in mice. Can J Physiol Pharmacol. 2018;96(1):45-50. 
doi: 10.1139/cjpp-2017-0228.
61. Rossato JI, Radiske A, Gonzalez MC, Apolinário G, de Araújo 
RLS, Bevilaqua LRM, et al. NMDARs control object recognition 
memory destabilization and reconsolidation. Brain Res Bull. 
2023;197:42-8. doi: 10.1016/j.brainresbull.2023.03.013.
62. Ledo A, Frade J, Barbosa RM, Laranjinha J. Nitric oxide in 
brain: diffusion, targets and concentration dynamics in 
hippocampal subregions. Mol Aspects Med. 2004;25(1-2):75-
89. doi: 10.1016/j.mam.2004.02.010.
63. Feil R, Kleppisch T. NO/cGMP-dependent modulation of 
synaptic transmission. Handb Exp Pharmacol. 2008(184):529-
60. doi: 10.1007/978-3-540-74805-2_16.
64. Jafari-Sabet M, Amiri S, Ataee R. Cross state-dependency of 
learning between tramadol and MK-801 in the mouse dorsal 
hippocampus: involvement of nitric oxide (NO) signaling 
pathway. Psychopharmacology (Berl). 2018;235(7):1987-99. 
doi: 10.1007/s00213-018-4897-5.
65. Jafari-Sabet M. NMDA receptor blockers prevents the 
facilitatory effects of post-training intra-dorsal hippocampal 
NMDA and physostigmine on memory retention of passive 
avoidance learning in rats. Behav Brain Res. 2006;169(1):120-
7. doi: 10.1016/j.bbr.2005.12.011.
66. Berrocoso E, Micó JA, Ugedo L. In vivo effect of tramadol on 
locus coeruleus neurons is mediated by alpha2-adrenoceptors 
and modulated by serotonin. Neuropharmacology. 
2006;51(1):146-53. doi: 10.1016/j.neuropharm.2006.03.013.
67. Barber J. Examining the use of tramadol hydrochloride as an 
antidepressant. Exp Clin Psychopharmacol. 2011;19(2):123-
30. doi: 10.1037/a0022721.
68. Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling 
pathways underlying the rapid antidepressant actions of 
ketamine. Neuropharmacology. 2012;62(1):35-41. doi: 
10.1016/j.neuropharm.2011.08.044.
69. Hashimoto K. Role of the mTOR signaling pathway in the 
rapid antidepressant action of ketamine. Expert Rev Neurother. 
2011;11(1):33-6. doi: 10.1586/ern.10.176.
70. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. 
mTOR-dependent synapse formation underlies the rapid 
antidepressant effects of NMDA antagonists. Science. 
2010;329(5994):959-64. doi: 10.1126/science.1190287.
71. Jernigan CS, Goswami DB, Austin MC, Iyo AH, Chandran 
A, Stockmeier CA, et al. The mTOR signaling pathway in 
the prefrontal cortex is compromised in major depressive 
disorder. Prog Neuropsychopharmacol Biol Psychiatry. 
2011;35(7):1774-9. doi: 10.1016/j.pnpbp.2011.05.010.
72. Yang C, Li WY, Yu HY, Gao ZQ, Liu XL, Zhou ZQ, et al. 
Tramadol pretreatment enhances ketamine-induced 
antidepressant effects and increases mammalian target ofrapamycin in rat hippocampus and prefrontal cortex. J Biomed 
Biotechnol. 2012;2012:175619. doi: 10.1155/2012/175619.
73. Yalcin I, Aksu F, Bodard S, Chalon S, Belzung C. 
Antidepressant-like effect of tramadol in the unpredictable 
chronic mild stress procedure: possible involvement of the 
noradrenergic system. Behav Pharmacol. 2007;18(7):623-31. 
doi: 10.1097/FBP.0b013e3282eff109.
74. Bloms-Funke P, Dremencov E, Cremers TI, Tzschentke TM. 
Tramadol increases extracellular levels of serotonin and 
noradrenaline as measured by in vivo microdialysis in the 
ventral hippocampus of freely-moving rats. Neurosci Lett. 
2011;490(3):191-5. doi: 10.1016/j.neulet.2010.12.049.
75. Baghishani F, Mohammadipour A, Hosseinzadeh H, Hosseini 
M, Ebrahimzadeh-Bideskan A. The effects of tramadol 
administration on hippocampal cell apoptosis, learning and 
memory in adult rats and neuroprotective effects of crocin. 
Metab Brain Dis. 2018;33(3):907-16. doi: 10.1007/s11011-
018-0194-6.
76. Elkerdasy HI, Shaheen NF. Histological and 
immunohistochemical study on the effect of tramadol 
abuse on cerebral cortex and hippocampus in male albino 
rabbits. Egypt J Histol. 2020;43(1):75-87. doi: 10.21608/
ejh.2019.10984.1103.
77. Hosseindoost S, Akbarabadi A, Sadat-Shirazi MS, Mousavi 
SM, Khalifeh S, Mokri A, et al. Effect of tramadol on apoptosis 
and synaptogenesis in hippocampal neurons: the possible role 
of µ-opioid receptor. Drug Dev Res. 2022;83(6):1425-33. doi: 
10.1002/ddr.21973.
78. Mehdizadeh H, Pourahmad J, Taghizadeh G, Vousooghi N, 
Yoonessi A, Naserzadeh P, et al. Mitochondrial impairments 
contribute to spatial learning and memory dysfunction 
induced by chronic tramadol administration in rat: protective 
effect of physical exercise. Prog Neuropsychopharmacol 
Biol Psychiatry. 2017;79(Pt B):426-33. doi: 10.1016/j.
pnpbp.2017.07.022.
79. Ahmadian-Moghadam H, Sadat-Shirazi MS, Azmoun S, 
Vafadoost R, Khalifeh S, Zarrindast MR. Tramadol treatment 
induces change in phospho-cyclic adenosine monophosphate 
response element-binding protein and delta and mu opioid 
receptors within hippocampus and amygdala areas of rat 
brain. Addict Health. 2021;13(3):165-75. doi: 10.22122/ahj.
v13i3.306.
80. Ali HA, Afifi M, Saber TM, Makki AA, Keshta AT, Baeshen 
M, et al. Neurotoxic, hepatotoxic and nephrotoxic 
effects of tramadol administration in rats. J Mol Neurosci. 
2020;70(12):1934-42. doi: 10.1007/s12031-020-01592-x.
81. Valian N, Sorayya M, Asadi S, Sherafati F, Ershad A, 
Savaheli S, et al. Preconditioning by ultra-low dose of 
tramadol reduces the severity of tramadol-induced seizure: 
contribution of glutamate receptors. Biomed Pharmacother. 
2021;133:111031. doi: 10.1016/j.biopha.2020.111031.
82. Sadek KM, Lebda MA, Abouzed TK, Nasr SM, El-Sayed Y. 
The molecular and biochemical insight view of lycopene in 
ameliorating tramadol-induced liver toxicity in a rat model: 
implication of oxidative stress, apoptosis, and MAPK signaling 
pathways. Environ Sci Pollut Res Int. 2018;25(33):33119-30. 
doi: 10.1007/s11356-018-3265-7.
83. Hakami AY, Alghamdi BS, Alshehri FS. Exploring the potential 
use of melatonin as a modulator of tramadol-induced 
rewarding effects in rats. Front Pharmacol 2024;15:1373746. 
doi: 10.3389/fphar.2024.1373746.
84. Ishola IO, Eneanya SU, Folarin OR, Awogbindin IO, Abosi AJ, 
Olopade JO, et al. Tramadol and codeine stacking/boosting 
dose exposure induced neurotoxic behaviors, oxidative 
stress, mitochondrial dysfunction, and neurotoxic genes in 
adolescent mice. Neurotox Res. 2022;40(5):1304-21. doi: 
10.1007/s12640-022-00539-x.
85. Mehranpour M, Hassani Moghaddam M, Abdollahifar MA, 
Aliaghaei A. Increase Apoptosis, Inflammation, and Oxidative 
Stress in the Choroid Plexus of Adult Male Rats by Tramadol 
Administration. 2022. Available from: https://ssrn.com/
abstract=4284418.
86. Kamranian H, Asoudeh H, Kamrani Sharif R, Taheri F, 
Hayes AW, Gholami M, et al. Neuroprotective potential of 
trimetazidine against tramadol-induced neurotoxicity: role of 
PI3K/Akt/mTOR signaling pathways. Toxicol Mech Methods. 
2023;33(7):607-23. doi: 10.1080/15376516.2023.2202785.
87. Gholami M, Hayes AW, Jamaati H, Sureda A, Motaghinejad 
M. Role of apoptosis and autophagy in mediating tramadolinduced neurodegeneration in the rat hippocampus. Mol Biol 
Rep. 2023;50(9):7393-404. doi: 10.1007/s11033-023-08641-9.
88. Prado VF, Janickova H, Al-Onaizi MA, Prado MA. Cholinergic 
circuits in cognitive flexibility. Neuroscience. 2017;345:130-
41. doi: 10.1016/j.neuroscience.2016.09.013.
89. Logue SF, Gould TJ. The neural and genetic basis of executive 
function: attention, cognitive flexibility, and response 
inhibition. Pharmacol Biochem Behav. 2014;123:45-54. doi: 
10.1016/j.pbb.2013.08.007.
90. Attoh-Mensah E, Léger M, Loggia G, Fréret T, Chavoix C, 
Schumann-Bard P. Effects of chronic tramadol administration 
on cognitive flexibility in mice. Psychopharmacology (Berl). 
2021;238(10):2883-93. doi: 10.1007/s00213-021-05903-x.
91. Said Shalaby A, Mohamed El-Seidy A, Aly Zayed M, Ragab 
Allam A. Does tramadol dependence impair cognitive 
functions? Int Clin Psychopharmacol. 2022;37(2):67-71. doi: 
10.1097/yic.0000000000000389.
92. Khoshsirat S, Abbaszadeh HA, Khoramgah MS, Darabi S, 
Mansouri V, Ahmady-Roozbahany N, et al. Protective effect of 
photobiomodulation therapy and bone marrow stromal stem 
cells conditioned media on pheochromocytoma cell line 12 
against oxidative stress induced by hydrogen peroxide. J Lasers 
Med Sci. 2019;10(3):163-70. doi: 10.15171/jlms.2019.26.
93. Circu ML, Aw TY. Reactive oxygen species, cellular redox 
systems, and apoptosis. Free Radic Biol Med. 2010;48(6):749-
62. doi: 10.1016/j.freeradbiomed.2009.12.022.
94. Poor Hassan M, Abdollahifar MA, Aliaghaei A, Tabeie F, 
Vafaei-Nezhad S, Norouzian M, et al. Photobiomodulation 
therapy improved functional recovery and overexpression 
of interleukins-10 after contusion spinal cord injury in rats. 
J Chem Neuroanat. 2021;117:102010. doi: 10.1016/j.
jchemneu.2021.102010.
95. Bameri B, Shaki F, Ahangar N, Ataee R, Samadi M, 
Mohammadi H. Evidence for the involvement of the 
dopaminergic system in seizure and oxidative damage 
induced by tramadol. Int J Toxicol. 2018;37(2):164-70. doi: 
10.1177/1091581817753607.
96. Mohamed HM, Mahmoud AM. Chronic exposure to the 
opioid tramadol induces oxidative damage, inflammation and 
apoptosis, and alters cerebral monoamine neurotransmitters 
in rats. Biomed Pharmacother. 2019;110:239-47. doi: 
10.1016/j.biopha.2018.11.141.
97. Ali HA, Afifi M, Saber TM, Makki AA, Keshta AT, Baeshen 
M, et al. Neurotoxic, hepatotoxic and nephrotoxic 
effects of tramadol administration in rats. J Mol Neurosci. 
2020;70(12):1934-42. doi: 10.1007/s12031-020-01592-x.
98. Mohamed TM, Ghaffar HM, El Husseiny RM. Effects of tramadol, 
clonazepam, and their combination on brain mitochondrial 
complexes. Toxicol Ind Health. 2015;31(12):1325-33. doi: 
10.1177/0748233713491814.
99. Kamranian H, Asoudeh H, Sharif RK, Taheri F, Hayes AW, 
Gholami M, et al. Neuroprotective potential of trimetazidine 
against tramadol-induced neurotoxicity: role of PI3K/Akt/mTOR signaling pathways. Toxicol Mech Methods. 
2023;33(7):607-23. doi: 10.1080/15376516.2023.2202785.
100. Shabani M, Jamali Z, Naserian A, Khezri S, Salimi A. 
Maintenance of mitochondrial function by sinapic acid 
protects against tramadol-induced toxicity in isolated 
mitochondria obtained from rat brain. Naunyn Schmiedebergs 
Arch Pharmacol. 2024;397(2):889-97. doi: 10.1007/s00210-
023-02648-6.
101. Kwon HS, Koh SH. Neuroinflammation in neurodegenerative 
disorders: the roles of microglia and astrocytes. Transl 
Neurodegener. 2020;9(1):42. doi: 10.1186/s40035-020-
00221-2.
102. Vafaei-Nezhad S, Niknazar S, Norouzian M, Abdollahifar 
MA, Aliaghaei A, Abbaszadeh HA. Therapeutics effects of 
[Pyr1] apelin-13 on rat contusion model of spinal cord injury: 
an experimental study. J Chem Neuroanat. 2021;113:101924. 
doi: 10.1016/j.jchemneu.2021.101924.
103. Sarhan NR, Taalab YM. Oxidative stress/PERK/apoptotic 
pathways interaction contribute to tramadol neurotoxicity in 
rat cerebral and cerebellar cortex and thyme enhances the 
antioxidant defense system: histological, immunohistochemical 
and ultrastructural study. Int J Sci Rep. 2018;4(6):124-41. doi: 
10.18203/issn.2454-2156.IntJSciRep20182083.
104. Huang Z, Zhou T, Sun X, Zheng Y, Cheng B, Li M, et al. 
Necroptosis in microglia contributes to neuroinflammation 
and retinal degeneration through TLR4 activation. Cell Death 
Differ. 2018;25(1):180-9. doi: 10.1038/cdd.2017.141.
105. Ghafari S, Golalipour MJ. Prenatal morphine exposure 
reduces pyramidal neurons in CA1, CA2 and CA3 subfields of 
mice hippocampus. Iran J Basic Med Sci. 2014;17(3):155-61. 
doi: 10.22038/ijbms.2014.2400.