Tramadol administration induced hippocampal cells apoptosis, astrogliosis, and microgliosis in juvenile and adult male mice, histological and immunohistochemical study

Hussein, Omar; Mola, Asmaa Fathi Abdel; Rateb, Amal

doi:10.1080/01913123.2019.1711480

Cited by 7 publications

(8 citation statements)

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“…Group 1: included mice that received physiological saline solution for 4 successive weeks and serving as control. Group 2: had mice that received tramadol (Tramadol tablets, each contains 225 mg tramadol hydrochloride, Mina-pharm, Egypt) orally by gastric intubation in a dose of 40 mg/kg body weight 36 dissolved in saline daily for 4 successive weeks.…”

Section: Methodsmentioning

confidence: 99%

Chronic exposure to tramadol induces cardiac inflammation and endothelial dysfunction in mice

Bakr

Radwan

Shaltout

et al. 2021

Sci Rep

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Tramadol is an opioid extensively used to treat moderate to severe pain; however, prolonged therapy is associated with several tissues damage. Chronic use of tramadol was linked to increased hospitalizations due to cardiovascular complications. Limited literature has described the effects of tramadol on the cardiovascular system, so we sought to investigate these actions and elucidate the underlying mechanisms. Mice received tramadol hydrochloride (40 mg/kg body weight) orally for 4 successive weeks. Oxidative stress, inflammation, and cardiac toxicity were assessed. In addition, eNOS expression was evaluated. Our results demonstrated marked histopathological alteration in heart and aortic tissues after exposure to tramadol. Tramadol upregulated the expression of oxidative stress and inflammatory markers in mice heart and aorta, whereas downregulated eNOS expression. Tramadol caused cardiac damage shown by the increase in LDH, Troponin I, and CK-MB activities in serum samples. Overall, these results highlight the risks of tramadol on the cardiovascular system.

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Section: Methodsmentioning

confidence: 99%

Chronic exposure to tramadol induces cardiac inflammation and endothelial dysfunction in mice

Bakr

Radwan

Shaltout

et al. 2021

Sci Rep

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“…Several studies support the role of GFAP upregulation in opioid dependence and tolerance [145,157,158]. Indeed, chronic drug abuse-induced astrogliosis is considered an innate immunity response to neurotoxicity and brain damage, which may lead to alterations in synaptogenesis and neurogenesis, apoptosis and/or necrosis [144,158]. Thus, in our study, increased GFAP expression is compatible with the signs of glial proliferation and hypertrophy observed in histopathological examination; these, in turn, are a response to opioid-induced injury (Figure 8).…”

Section: Repeated Exposure To Tramadol and Tapentadol Alters The Exprmentioning

confidence: 98%

“…Opioid brain signaling and information processing were found to induce the activation of glial cells, especially astrocytes, by direct MOR stimulation in astrocyte membranes [144,145]. GS is highly expressed in astrocytes, for which it serves as an astrocytic marker [146].…”

Section: Repeated Exposure To Tramadol and Tapentadol Alters The Exprmentioning

confidence: 99%

“…In the present study, the protein content of GFAP, another astrocyte activation biomarker, was also found to be increased in brain cortex extracts upon exposure to the lowest and intermediate opioid doses (Figure 4). GFAP hippocampal immunoreactivity increased in juvenile and adult mice treated with 40 mg tramadol/kg/day for 1 month, which, along with astrocytic swelling, was reported as astrogliosis [144]. Morphine exposure has been reported to lead to similar effects in different brain areas, including ventral tegmental area, nucleus accumbens, striatum, and frontal cortex [145,157,158].…”

Section: Repeated Exposure To Tramadol and Tapentadol Alters The Exprmentioning

confidence: 99%

“…Neuronal degeneration and histological changes have been correlated with glucose metabolism alterations and with the bioenergetic crisis discussed in Section 3.4 [55,60]. Cellular infiltrates are also mentioned in these studies [58,60,164], as well as gliosis, satellitosis, and microglial and oligodendrocyte proliferation [58,62,144,164]. Vascular dilatation and congestion, hemorrhage, and brain edema are also cited [58][59][60][61][62]70,164,166].…”

Section: Repeated Exposure To Tramadol and Tapentadol Leads To Histopmentioning

confidence: 99%

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Repeated Administration of Clinically Relevant Doses of the Prescription Opioids Tramadol and Tapentadol Causes Lung, Cardiac, and Brain Toxicity in Wistar Rats

et al. 2021

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Tramadol and tapentadol, two structurally related synthetic opioid analgesics, are widely prescribed due to the enhanced therapeutic profiles resulting from the synergistic combination between μ-opioid receptor (MOR) activation and monoamine reuptake inhibition. However, the number of adverse reactions has been growing along with their increasing use and misuse. The potential toxicological mechanisms for these drugs are not completely understood, especially for tapentadol, owing to its shorter market history. Therefore, in the present study, we aimed to comparatively assess the putative lung, cardiac, and brain cortex toxicological damage elicited by the repeated exposure to therapeutic doses of both prescription opioids. To this purpose, male Wistar rats were intraperitoneally injected with single daily doses of 10, 25, and 50 mg/kg tramadol or tapentadol, corresponding to a standard analgesic dose, an intermediate dose, and the maximum recommended daily dose, respectively, for 14 consecutive days. Such treatment was found to lead mainly to lipid peroxidation and inflammation in lung and brain cortex tissues, as shown through augmented thiobarbituric acid reactive substances (TBARS), as well as to increased serum inflammation biomarkers, such as C reactive protein (CRP) and tumor necrosis factor-α (TNF-α). Cardiomyocyte integrity was also shown to be affected, since both opioids incremented serum lactate dehydrogenase (LDH) and α-hydroxybutyrate dehydrogenase (α-HBDH) activities, while tapentadol was associated with increased serum creatine kinase muscle brain (CK-MB) isoform activity. In turn, the analysis of metabolic parameters in brain cortex tissue revealed increased lactate concentration upon exposure to both drugs, as well as augmented LDH and creatine kinase (CK) activities following tapentadol treatment. In addition, pneumo- and cardiotoxicity biomarkers were quantified at the gene level, while neurotoxicity biomarkers were quantified both at the gene and protein levels; changes in their expression correlate with the oxidative stress, inflammatory, metabolic, and histopathological changes that were detected. Hematoxylin and eosin (H & E) staining revealed several histopathological alterations, including alveolar collapse and destruction in lung sections, inflammatory infiltrates, altered cardiomyocytes and loss of striation in heart sections, degenerated neurons, and accumulation of glial and microglial cells in brain cortex sections. In turn, Masson’s trichrome staining confirmed fibrous tissue deposition in cardiac tissue. Taken as a whole, these results show that the repeated administration of both prescription opioids extends the dose range for which toxicological injury is observed to lower therapeutic doses. They also reinforce previous assumptions that tramadol and tapentadol are not devoid of toxicological risk even at clinical doses.

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Effect of tramadol on apoptosis and synaptogenesis in hippocampal neurons: The possible role of µ‐opioid receptor

Hosseindoost

Akbarabadi

Sadat‐Shirazi

et al. 2022

Drug Development Research

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Tramadol is a synthetic opioid with centrally acting analgesic activity that alleviates moderate to severe pain and treats withdrawal symptoms of the other opioids. Like other opioid drugs, tramadol abuse has adverse effects on central nervous system components. Chronic administration of tramadol induces maladaptive plasticity in brain structures responsible for cognitive function, such as the hippocampus. However, the mechanisms by which tramadol induces these alternations are not entirely understood. Here, we examine the effect of tramadol on apoptosis and synaptogenesis of hippocampal neuronal in vitro. First, the primary culture of hippocampal neurons from neonatal rats was established, and the purity of the neuronal cells was verified by immunofluorescent staining. To evaluate the effect of tramadol on neuronal cell viability MTT assay was carried out. The western blot analysis technique was performed for the assessment of apoptosis and synaptogenesis markers. Results show that chronic exposure to tramadol reduces cell viability of neuronal cells and naloxone reverses this effect. Also, the level of caspase‐3 significantly increased in tramadol‐exposed hippocampal neurons. Moreover, tramadol downregulates protein levels of synaptophysin and stathmin as synaptogenesis markers. Interestingly, the effects of tramadol were abrogated by naloxone treatment. These findings suggest that tramadol can induce neurotoxicity in hippocampal neuronal cells, and this effect was partly mediated through opioid receptors.

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Tramadol administration induced hippocampal cells apoptosis, astrogliosis, and microgliosis in juvenile and adult male mice, histological and immunohistochemical study

Cited by 7 publications

References 58 publications

Chronic exposure to tramadol induces cardiac inflammation and endothelial dysfunction in mice

Chronic exposure to tramadol induces cardiac inflammation and endothelial dysfunction in mice

Repeated Administration of Clinically Relevant Doses of the Prescription Opioids Tramadol and Tapentadol Causes Lung, Cardiac, and Brain Toxicity in Wistar Rats

Effect of tramadol on apoptosis and synaptogenesis in hippocampal neurons: The possible role of µ‐opioid receptor

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