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

Abstract

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.

Profiling neuronal methylome and hydroxymethylome of opioid use disorder in the human orbitofrontal cortex

“…HBB has been reported in neurodegenerative neurons associated with Parkinson’s 42 , and Alzheimer’s 43 . Neurodegeneration has been observed in opioid use studies 44 , 45 . Further, hemoglobin acts as an oxygen-storage molecule in hypoxia, which is suggested to be induced by opioids in rodents 46 , indicating a potential increase in brain hypoxia in individuals with OUD.…”

Ameliorative Effects of FMRFamide on 3,4-Methylenedioxyl-Methamphetamine /Tramadol-Induced Neurodegeneration in the Hippocampus

“…Tramadol is converted by CYP450 enzymes 3A4 and 2D6 into 3 major metabolites; Odesmethyltramadol (M1), N, N-didesmethyltramadol (M3) and N, O-didesmethyltramadol (M5), 2 of which are active (7). Tramadol administration impairs memory function in rodent models by activation of μ-opioid receptors (8,9). Chronic administration of tramadol has been associated with histological abnormalities such as increasing apoptosis in rat cerebral cortex and hippocampus (10,11).…”