## 4 Discussion
Activation of IR may modify GABAergic synaptic transmission, directly affecting seizure susceptibility and EEG recording patterns [56]. Moreover, substances that influence IR, such as agmatine, may provide further valuable information for addressing withdrawal symptoms from opioids like tramadol by modulating receptor interactions in the CNS [57]. This indicates that employing imidazoline receptor modulators could decrease the negative neurological consequences, potentially detectable by EEG alterations after withdrawal or excessive exposure to tramadol [58]. EEG can provide important data regarding the brain dopaminergic systems in normal and pathological situations [59; 60; 61]. EEG can also provide important data in both human addiction and experimental addiction research [62; 63]. By focusing on amplitude and frequency distributions, rather than on coherence, or time-frequency analysis, we directly assessed the excitability of the neural networks, in order to demonstrate noteworthy shifts in response to the administered treatment. Moreover, we considered that amplitude-based metrics offer a more comprehensive picture of the excitatory and inhibitory balance within the cortical networks during depressive states. This distinction may be crucial as the alterations we investigated in the recorded patterns correlate with behavioral outcomes. An increasing body of evidence suggests that CPP experiments demonstrate that tramadol can induce rewarding effects, as seen by alterations in EEG patterns linked to dopaminergic activity within the mesolimbic system [64]. The visualization of alterations in dopamine levels using EEG is therefore crucial, as it offers insight into the neurological foundations of tramadol's propensity for dependency and addiction. The regulation of EEG activity concerning tramadol covers its long-term effects and combinations with other substances. The co-administration of nalbuphine, an opioid antagonist, has been demonstrated to reduce tramadol's rewarding effects while augmenting its analgesic characteristics, indicating that EEG alterations can monitor the complicated relationship between pain relief and reward pathways [42]. The dynamics of neurotransmitters assessed via EEG can provide insights into the behavioral manifestations of these interactions, underscoring the further need of employing EEG in pharmacological investigations of tramadol to comprehend its overall impact on the CNS. Another future direction would be the integration of EEG patterns within imagistic exploratory protocols. IR ligands may affect central pain processing, and these effects could potentially be detected with magnetic resonance imaging (MRI) as alterations in brain activity patterns that are linked to pain perception [65; 66]. As imaging modalities like functional MRI (fMRI) advance, the capacity to visualize receptor interactions and their effects on pain pathways will improve. Over the last decades, MRI scans have been essential in measuring the physiological impacts of tramadol and evaluating its effectiveness in modifying brain processes. In a recent study, [PERSON] et al. used baseline MRI images to monitor alterations in gastrointestinal motility induced by tramadol, illustrating the efficacy of MRI in detecting neurological and physiological modifications caused by medication [67]. We also consider that further integration of MRI in chronic pain research alongside EEG monitoring will clarify the structural and functional alterations in the brain linked to extended tramadol consumption while offering improved understanding of the function of IR in pain regulation. Tramadol may also enhance mood, likely due to its interaction with monoamine neurotransmitter systems and IR, highlighting the risk for dependence [68]. Improved comprehension of these connections using MRI can better elucidate how tramadol affects brain networks associated with mood and reward.