Skip to main content

Advertisement

SpringerLink
Log in

Chronic exposure to methadone induces activated microglia and astrocyte and cell death in the cerebellum of adult male rats

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Methadone is a centrally-acting synthetic opioid analgesic widely used in the methadone maintenance therapy (MMT) programs throughout the world. Considering its neurotoxic effects particularly on the cerebellum, this study aims to address the behavioral and histological alterations in the cerebellar cortex associated with methadone administration. Twenty-four adult male albino rats were randomized into two groups of control and methadone treatment. Methadone was subcutaneously administered (2.5–10 mg/kg) once a day for two consecutive weeks. The functional and structural changes in the cerebellum were compared to the control group. Our data revealed that treating rats with methadone not only induced cerebellar atrophy, but also prompted the actuation of microgliosis, astrogliosis, and apoptotic biomarkers. We further demonstrated that treating rats with methadone increased complexity of astrocyte processes and decreased complexity of microglia processes. Our result showed that methadone impaired motor coordination and locomotor performance and neuromuscular activity. Additionally, relative gene expression of TNF-α, caspase-3 and RIPK3 increased significantly due to methadone. Our findings suggest that methadone administration has a neurodegenerative effect on the cerebellar cortex via dysregulation of microgliosis, astrogliosis, apoptosis, and neuro-inflammation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data availability

The data supporting the findings of this study are available on request from the corresponding author.

References

  • Ahmad-Molaei L et al (2018) Delay-dependent impairments in memory and motor functions after acute methadone overdose in rats. Front Pharmacol 9:1023

    Article  Google Scholar 

  • Ahmad-Molaei L et al (2021) Time-dependent changes in the serum levels of neurobiochemical factors after acute methadone overdose in adolescent male rat. Cell Mol Neurobiol 41(8):1635–1649

  • Andersen JM et al (2011) Long-term methadone treatment impairs novelty preference in rats both when present and absent in brain tissue. Pharmacol Biochem Behav 98(3):412–416

    Article  CAS  Google Scholar 

  • Aschner M (1998) Astrocytes as mediators of immune and inflammatory responses in the CNS. Neurotoxicology 19(2):269–281

    CAS  Google Scholar 

  • Balasingam V et al (1994) Reactive astrogliosis in the neonatal mouse brain and its modulation by cytokines. J Neurosci 14(2):846–856

    Article  CAS  Google Scholar 

  • Barash JA, Somerville N, DeMaria A Jr (2017) Cluster of an unusual amnestic syndrome—Massachusetts, 2012–2016. MMWR Morb Mortal Wkly Rep 66(3):76

    Article  Google Scholar 

  • Berridge KC (2007) The debate over dopamine’s role in reward: the case for incentive salience. Psychopharmacology 191(3):391–431

    Article  CAS  Google Scholar 

  • Betts AM, Ritter JL, Kubal WS (2012) Reversible delayed posthypoxic leukoencephalopathy after drug overdose: MRI findings in a collection of patients. Emerg Radiol 19(2):165–173

    Article  Google Scholar 

  • Bowie A, O’Neill LA (2000) The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for pro-inflammatory interleukins and microbial products. J Leukoc Biol 67(4):508–514

    Article  CAS  Google Scholar 

  • Bsibsi M et al (2002) Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 61(11):1013–1021

    Article  CAS  Google Scholar 

  • Campbell IL et al (1993) Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci 90(21):10061–10065

    Article  CAS  Google Scholar 

  • Caritis SN, Panigrahy A (2019) Opioids affect the fetal brain: reframing the detoxification debate. Am J Obstet Gynecol 221(6):602–608

    Article  CAS  Google Scholar 

  • Cerase A et al (2011) Methadone-Induced Toxic Leukoencephalopathy: Diagnosis and Follow-up by Magnetic Resonance Imaging Including Diffusion-Weighted Imaging and Apparent Diffusion Coefficient Maps. J Neuroimaging 21(3):283–286

    Article  Google Scholar 

  • Chiang C-S et al (1994) Reactive gliosis as a consequence of interleukin-6 expression in the brain: studies in transgenic mice. Dev Neurosci 16(3–4):212–221

    Article  CAS  Google Scholar 

  • Corkery JM et al (2004) The effects of methadone and its role in fatalities. Hum Psychopharmacol Clin Exp 19(8):565–576

    Article  CAS  Google Scholar 

  • Corré J, Pillot J, Hilbert G (2013) Methadone-induced toxic brain damage. Case Rep Radiol 2013:602981

    Google Scholar 

  • Crepel F, Dhanjal S (1982) Cholinergic mechanisms and neurotransmission in the cerebellum of the rat. An in vitro Study. Brain Research 244(1):59–68

    Article  CAS  Google Scholar 

  • Crone JS et al (2015) Impaired consciousness is linked to changes in effective connectivity of the posterior cingulate cortex within the default mode network. Neuroimage 110:101–109

    Article  Google Scholar 

  • Davis BM et al (2017) Characterizing microglia activation: a spatial statistics approach to maximize information extraction. Sci Rep 7(1):1–12

    Article  Google Scholar 

  • Doi S et al (2016) Characterization of methadone as a β-arrestin-biased μ-opioid receptor agonist. Mol Pain 12:1744806916654146

    Article  Google Scholar 

  • Dong C, Davis RJ, Flavell RA (2002) MAP kinases in the immune response. Annu Rev Immunol 20(1):55–72

    Article  CAS  Google Scholar 

  • Dutta R et al (2012) Morphine modulation of toll-like receptors in microglial cells potentiates neuropathogenesis in a HIV-1 model of coinfection with pneumococcal pneumoniae. J Neurosci 32(29):9917–9930

    Article  CAS  Google Scholar 

  • Eap CB, Buclin T, Baumann P (2002) Interindividual variability of the clinical pharmacokinetics of methadone. Clin Pharmacokinet 41(14):1153–1193

    Article  CAS  Google Scholar 

  • Ebert B, Andersen S, Krogsgaard-Larsen P (1995) Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord. Neurosci Lett 187(3):165–168

    Article  CAS  Google Scholar 

  • Eddleston M, Mucke L (1993) Molecular profile of reactive astrocytes—implications for their role in neurologic disease. Neuroscience 54(1):15–36

    Article  CAS  Google Scholar 

  • Eidson LN, Murphy AZ (2013a) Blockade of Toll-like receptor 4 attenuates morphine tolerance and facilitates the pain relieving properties of morphine. J Neurosci 33(40):15952–15963

    Article  CAS  Google Scholar 

  • Eidson LN, Murphy AZ (2013b) Persistent peripheral inflammation attenuates morphine-induced periaqueductal gray glial cell activation and analgesic tolerance in the male rat. J Pain 14(4):393–404

    Article  CAS  Google Scholar 

  • Enari M et al (1998) A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391(6662):43–50

    Article  CAS  Google Scholar 

  • Eng LF, Ghirnikar RS (1994) GFAP and astrogliosis. Brain Pathol 4(3):229–237

    Article  CAS  Google Scholar 

  • Farid W et al (2008) The effects of maternally administered methadone, buprenorphine and naltrexone on offspring: review of human and animal data. Curr Neuropharmacol 6(2):125–150

    Article  CAS  Google Scholar 

  • Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28(3):138–145

    Article  CAS  Google Scholar 

  • Farina C et al (2005) Preferential expression and function of Toll-like receptor 3 in human astrocytes. J Neuroimmunol 159(1–2):12–19

    Article  CAS  Google Scholar 

  • Fjelldal MF et al (2019) Opioid receptor-mediated changes in the NMDA receptor in developing rat and chicken. Int J Dev Neurosci 78:19–27

    Article  CAS  Google Scholar 

  • Foster DJ et al (2000) Steady-state pharmacokinetics of (R)-and (S)-methadone in methadone maintenance patients. Br J Clin Pharmacol 50(5):427–440

    Article  CAS  Google Scholar 

  • Foster DJ et al (2004) Population pharmacokinetics of (R)-,(S)-and rac-methadone in methadone maintenance patients. Br J Clin Pharmacol 57(6):742–755

    Article  CAS  Google Scholar 

  • Gessi S et al (2016) The activation of μ-opioid receptor potentiates LPS-induced NF-kB promoting an inflammatory phenotype in microglia. FEBS Lett 590(17):2813–2826

    Article  CAS  Google Scholar 

  • Ghorbani Z et al (2022) Melittin administration ameliorates motor function, prevents apoptotic cell death and protects Purkinje neurons in the rat model of cerebellar ataxia induced by 3-Acetylpyridine. Toxicon 205:57–66

    Article  CAS  Google Scholar 

  • Golalipour MJ, Ghafari S (2012) Purkinje cells loss in off spring due to maternal morphine sulfate exposure: a morphometric study. Anat Cell Biol 45(2):121–127

    Article  Google Scholar 

  • Gorina R et al (2009) Astrocytes are very sensitive to develop innate immune responses to lipid-carried short interfering RNA. Glia 57(1):93–107

    Article  Google Scholar 

  • Graham A et al (2002) Immunohistochemical localisation of nicotinic acetylcholine receptor subunits in human cerebellum. Neuroscience 113(3):493–507

    Article  CAS  Google Scholar 

  • Hauser K, Matthes J (2017) Medical students’ medication communication skills regarding drug prescription—a qualitative analysis of simulated physician-patient consultations. Eur J Clin Pharmacol 73(4):429–435

    Article  Google Scholar 

  • Hernandez MR et al (2002) Differential gene expression in astrocytes from human normal and glaucomatous optic nerve head analyzed by cDNA microarray. Glia 38(1):45–64

    Article  Google Scholar 

  • Horvath RJ, DeLeo JA (2009) Morphine enhances microglial migration through modulation of P2X4 receptor signaling. J Neurosci 29(4):998–1005

    Article  CAS  Google Scholar 

  • Hostenbach S et al (2014) Astrocyte loss and astrogliosis in neuroinflammatory disorders. Neurosci Lett 565:39–41

    Article  CAS  Google Scholar 

  • Hu S et al (2002) Morphine induces apoptosis of human microglia and neurons. Neuropharmacology 42(6):829–836

    Article  CAS  Google Scholar 

  • Jack CS et al (2005) TLR signaling tailors innate immune responses in human microglia and astrocytes. J Immunol 175(7):4320–4330

    Article  CAS  Google Scholar 

  • Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298(5600):1911–1912

    Article  CAS  Google Scholar 

  • Klein MA et al (1997) Impaired neuroglial activation in interleukin-6 deficient mice. Glia 19(3):227–233

    Article  CAS  Google Scholar 

  • Klenowski P, Morgan M, Bartlett SE (2015) The role of δ-opioid receptors in learning and memory underlying the development of addiction. Br J Pharmacol 172(2):297–310

    Article  CAS  Google Scholar 

  • Le Merrer J et al (2009) Reward processing by the opioid system in the brain. Physiol Rev 89(4):1379–1412

    Article  Google Scholar 

  • Lin S-L et al (2015) Predicting neuroinflammation in morphine tolerance for tolerance therapy from immunostaining images of rat spinal cord. PLoS ONE 10(10):e0139806

    Article  Google Scholar 

  • Machelska H, Celik MÖ (2020) Opioid receptors in immune and glial cells—implications for pain control. Front Immunol 11:300

    Article  CAS  Google Scholar 

  • Maduna T et al (2019) Microglia express mu opioid receptor: insights from transcriptomics and fluorescent reporter mice. Front Psych 9:726

    Article  Google Scholar 

  • Mao Y (2016) Nearest neighbor distances calculation with ImageJ.

  • Mark GP et al (2011) Cholinergic modulation of mesolimbic dopamine function and reward. Physiol Behav 104(1):76–81

    Article  CAS  Google Scholar 

  • Mashima T et al (1995a) Identification of actin as a substrate of ICE and an ICE-like protease and involvement of an ICE-like protease but not ICE in VP-16-induced U937 apoptosis. Biochem Biophys Res Commun 217(3):1185–1192

    Article  CAS  Google Scholar 

  • Mashima T et al (1995b) Aspartate-based inhibitor of interleukin-1β-converting enzyme prevents antitumor agent-induced apoptosis in human myeloid leukemia U937 cells. Biochem Biophys Res Commun 209(3):907–915

    Article  CAS  Google Scholar 

  • Merighi S et al (2012) Cannabinoid CB2 receptor attenuates morphine-induced inflammatory responses in activated microglial cells. Br J Pharmacol 166(8):2371–2385

    Article  CAS  Google Scholar 

  • Merighi S et al (2013) Morphine mediates a proinflammatory phenotype via μ-opioid receptor–PKCɛ–Akt–ERK1/2 signaling pathway in activated microglial cells. Biochem Pharmacol 86(4):487–496

    Article  CAS  Google Scholar 

  • Middaugh LD, Ingram DK, Reynolds MA (1983) Methadone effects on locomotor activity of young and aged mice. Neurobiol Aging 4(2):157–161

    Article  CAS  Google Scholar 

  • Mills F et al (2008) Severe cerebellitis following methadone poisoning. Pediatr Radiol 38(2):227–229

    Article  Google Scholar 

  • Minagar A et al (2002) The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. J Neurol Sci 202(1–2):13–23

    Article  CAS  Google Scholar 

  • Mittal M et al (2010) Methadone-induced delayed posthypoxic encephalopathy: clinical, radiological, and pathological findings. Case Rep Med

  • Moghaddam MH et al (2021) Elderberry diet ameliorates motor function and prevents oxidative stress-induced cell death in rat models of Huntington disease. Brain Res 1762:147444

    Article  CAS  Google Scholar 

  • Monnelly VJ et al (2018) Prenatal methadone exposure is associated with altered neonatal brain development. NeuroImage Clin 18:9–14

  • Moreno-Rius J (2019) Opioid addiction and the cerebellum. Neurosci Biobehav Rev 107:238–251

    Article  CAS  Google Scholar 

  • Neustadt A, Frostholm A, Rotter A (1988) On the cellular localization of cerebellar muscarinic receptors: an autoradiographic analysis of weaver, reeler, Purkinje cell degeneration and staggerer mice. Brain Res Bull 20(2):163–172

    Article  CAS  Google Scholar 

  • Newby-Schmidt M, Norton S (1981) Development of opiate tolerance in the chick embyro. Pharmacol Biochem Behav 15(5):773–778

    Article  CAS  Google Scholar 

  • Nicholson DW et al (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376(6535):37–43

    Article  CAS  Google Scholar 

  • Nylander E et al (2021) The effects of morphine, methadone, and fentanyl on mitochondria: A live cell imaging study. Brain Res Bull 171:126–134

    Article  CAS  Google Scholar 

  • Ocek T et al (2015) Psychodermatology: knowledge, awareness, practicing patterns, and attitudes of dermatologists in Turkey. The primary care companion for CNS disorders. 17(2)

  • Park C et al (2006) TLR3-mediated signal induces proinflammatory cytokine and chemokine gene expression in astrocytes: differential signaling mechanisms of TLR3-induced IP-10 and IL-8 gene expression. Glia 53(3):248–256

    Article  Google Scholar 

  • Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50(4):427–434

    Article  Google Scholar 

  • Pekny M, Pekna M (2016) Reactive gliosis in the pathogenesis of CNS diseases. Biochim Biophys Acta Mol Basis Dis 1862(3):483–491

  • Pekny M, Pekna M (2014) Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol Rev 94(4):1077–1098

    Article  Google Scholar 

  • Perez-Alvarez S et al (2010) Methadone induces necrotic-like cell death in SH-SY5Y cells by an impairment of mitochondrial ATP synthesis. Biochim Biophys Acta Mol Basis Dis 1802(11):1036–1047

  • Plonsky M, Freeman PR (1982) The effects of methadone on the social behavior and activity of the rat. Pharmacol Biochem Behav 16(4):569–571

    Article  CAS  Google Scholar 

  • Rabchevsky AG et al (1998) A role for transforming growth factor α as an inducer of astrogliosis. J Neurosci 18(24):10541–10552

    Article  CAS  Google Scholar 

  • Rando J et al (2016) Methadone overdose causing acute cerebellitis and multi-organ damage. Am J Emerg Med 34(2):343. e1–343. e3

  • Ranjbar H et al (2021) Addiction and the cerebellum with a focus on actions of opioid receptors. Neurosci Biobehav Rev 131:229–247

    Article  CAS  Google Scholar 

  • Rinaldo L, Hansel C (2013) Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber–Purkinje cell synapses via cannabinoid signaling. Proc Natl Acad Sci 110(27):11181–11186

    Article  CAS  Google Scholar 

  • Robinson SE (2002) Effects of perinatal buprenorphine and methadone exposures on striatal cholinergic ontogeny. Neurotoxicol Teratol 24(2):137–142

    Article  CAS  Google Scholar 

  • Roeckel L-A et al (2016) Opioid-induced hyperalgesia: cellular and molecular mechanisms. Neuroscience 338:160–182

    Article  CAS  Google Scholar 

  • Romano J, Shih T-M (1983) Cholinergic mechanisms of analgesia produced by physostigmine, morphine and cold water swimming. Neuropharmacology 22(7):827–833

    Article  CAS  Google Scholar 

  • Rossi D (2015) Astrocyte physiopathology: at the crossroads of intercellular networking, inflammation and cell death. Prog Neurobiol 130:86–120

    Article  CAS  Google Scholar 

  • Sanchez ES et al (2008) Opioid addiction and pregnancy: perinatal exposure to buprenorphine affects myelination in the developing brain. Glia 56(9):1017–1027

    Article  Google Scholar 

  • Shields LB et al (2007) Methadone toxicity fatalities: a review of medical examiner cases in a large metropolitan area. J Forensic Sci 52(6):1389–1395

    Article  Google Scholar 

  • Sriram K et al (2004) Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo? J Biol Chem 279(19):19936–19947

    Article  CAS  Google Scholar 

  • Steidl S et al (2017) Opioid-induced rewards, locomotion, and dopamine activation: A proposed model for control by mesopontine and rostromedial tegmental neurons. Neurosci Biobehav Rev 83:72–82

    Article  CAS  Google Scholar 

  • Stinson FS et al (2005) Comorbidity between DSM-IV alcohol and specific drug use disorders in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Drug Alcohol Depend 80(1):105–116

    Article  Google Scholar 

  • Suk K et al (2001) Activation-induced cell death of rat astrocytes. Brain Res 900(2):342–347

    Article  CAS  Google Scholar 

  • Sultan F, Glickstein M (2007) The cerebellum: comparative and animal studies. The Cerebellum 6(3):168–176

    Article  Google Scholar 

  • Sun H et al (2010) Detour behavior changes associated with prenatal morphine exposure in 11-day-old chicks. Int J Dev Neurosci 28(3):239–243

    Article  CAS  Google Scholar 

  • Takayasu Y et al (2003) Muscarine-induced increase in frequency of spontaneous EPSCs in Purkinje cells in the vestibulo-cerebellum of the rat. J Neurosci 23(15):6200–6208

    Article  CAS  Google Scholar 

  • Tsien J, Huerta PT, Tonegawa S (1996) The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87:1327–1338

    Article  CAS  Google Scholar 

  • Tu H et al (2020) The role of the M1/M2 microglia in the process from cancer pain to morphine tolerance. Tissue Cell 101438

  • Tumati S et al (2012) Tachykinin NK1 receptor antagonist co-administration attenuates opioid withdrawal-mediated spinal microglia and astrocyte activation. Eur J Pharmacol 684(1–3):64–70

    Article  CAS  Google Scholar 

  • Vacca V et al (2013) Botulinum toxin A increases analgesic effects of morphine, counters development of morphine tolerance and modulates glia activation and μ opioid receptor expression in neuropathic mice. Brain Behav Immun 32:40–50

    Article  CAS  Google Scholar 

  • Vallés SL et al (2004) Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. Brain Pathol 14(4):365–371

    Article  Google Scholar 

  • Verkhratsky A, Butt A (2013) Glial physiology and pathophysiology. John Wiley & Sons

  • Vernadakis A et al (1990) Function of opioids early in embryogenesis. Ann N Y Acad Sci 579(1):109–122

    Article  CAS  Google Scholar 

  • Wang L et al (1994) Ich-1, an Ice/ced-3-related gene, encodes both positive and negative regulators of programmed cell death. Cell 78(5):739–750

    Article  CAS  Google Scholar 

  • Wang Y, Han T-Z (2009) Prenatal exposure to heroin in mice elicits memory deficits that can be attributed to neuronal apoptosis. Neuroscience 160(2):330–338

    Article  CAS  Google Scholar 

  • Weinberger L et al (1994) Delayed postanoxic demyelination and arylsulfatase-A pseudodeficiency. Neurology 44(1):152–152

    Article  CAS  Google Scholar 

  • Williams MJ, Adinoff B (2008) The role of acetylcholine in cocaine addiction. Neuropsychopharmacology 33(8):1779–1797

    Article  CAS  Google Scholar 

  • Winter CG et al (1995) A role for ciliary neurotrophic factor as an inducer of reactive gliosis, the glial response to central nervous system injury. Proc Natl Acad Sci 92(13):5865–5869

    Article  CAS  Google Scholar 

  • Wu VW et al (2001) Perinatal opioids reduce striatal nerve growth factor content in rat striatum. Eur J Pharmacol 414(2–3):211–214

    Article  CAS  Google Scholar 

  • Yokoyama Y et al (1997) CPP32 activation during dolichyl phosphate-induced apoptosis in U937 leukemia cells. FEBS Lett 412(1):153–156

    Article  CAS  Google Scholar 

  • Yoshida A et al (2000) Opioid analgesic-induced apoptosis and caspase-independent cell death in human lung carcinoma A549 cells. Int J Mol Med 6(3):329–364

    CAS  Google Scholar 

  • Zadina JE et al (2016) Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine. Neuropharmacology 105:215–227

    Article  CAS  Google Scholar 

  • Zagon IS, McLaughlin PJ (1982) Comparative effects of postnatal undernutrition and methadone exposure on protein and nucleic acid contents of the brain and cerebellum in rats. Dev Neurosci 5(5–6):385–393

    Article  CAS  Google Scholar 

  • Zhang Q et al (2013) DAMPs and autophagy: cellular adaptation to injury and unscheduled cell death. Autophagy 9(4):451–458

    Article  CAS  Google Scholar 

  • Zöllner C et al (2008) Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain. J Clin Investig 118(3):1065–1073

    Google Scholar 

Download references

Acknowledgements and founding information

We are thankful for the funding provided by Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, and Tehran, Iran.

Author information

Authors and Affiliations

  1. Department of Biology, Faculty of Biological Science, North Tehran Branch, Islamic Azad University, Tehran, Iran

    Naghmeh Zamani

  2. Department of Microbiology, Faculty of Biological Science, North Tehran Branch, Islamic Azad University, Tehran, Iran

    Laya Takbiri Osgoei

  3. Hearing Disorders Research Center, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Abbas Aliaghaei

  4. Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Abbas Aliaghaei

  5. Department of Clinical Toxicology, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Nasim Zamani & Hossein Hassanian-Moghaddam

Authors
  1. Naghmeh Zamani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laya Takbiri Osgoei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abbas Aliaghaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nasim Zamani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hossein Hassanian-Moghaddam
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Abbas Aliaghaei, Laya Takbiri Osgoei: study concepts, literature research, clinical studies, data analysis, experimental studies, manuscript writing, and review; Naghmeh Zamani: study design, literature research, experimental studies, and manuscript editing; Naghmeh Zamani, Nasim Zamani: definition of intellectual content, clinical studies, data acquisition, and statistical analysis; Hossein Hassanian Moghaddam: data acquisition, manuscript preparation, and data analysis; Abbas Aliaghaei, Laya Takbiri Osgoei: data acquisition and statistical analysis.

All authors have read and approved the submission of the manuscript.

Corresponding authors

Correspondence to Laya Takbiri Osgoei or Abbas Aliaghaei.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The Shahid Beheshti University of Medical Sciences’ ethics committee approved this animal experiment (IR SBMU.MSP.REC.1398.292).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zamani, N., Osgoei, L.T., Aliaghaei, A. et al. Chronic exposure to methadone induces activated microglia and astrocyte and cell death in the cerebellum of adult male rats. Metab Brain Dis 38, 323–338 (2023). https://doi.org/10.1007/s11011-022-01108-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-022-01108-z

Keywords

Search

Navigation