Methylphenidate and High-Intensity Interval Training Alone and in Combination Ameliorate the Tramadol-Induced Cardiac Side Effects in Male Rats: The Role of Oxidative Stress and Mitochondria Function

Tramadol, a widely prescribed analgesic for moderate to severe pain, is associated with significant cardiovascular risks. This study investigated the effects of high-intensity interval training (HIIT), methylphenidate (MPH), and their combination on oxidative stress and mitochondrial quality in the hearts of male Wistar rats subjected to long-term tramadol treatment. Experimental groups included control (CTL), MPH, tramadol (TR), HIIT, MPH+HIIT, TR+HIIT, and MPH+TR+HIIT. Rats underwent HIIT; 5 days per week for 8 weeks. Real-time PCR was used to quantify MFN-2, DRP-1, PINK-1, and Parkin mRNA levels. Superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities, and malondialdehyde (MDA) levels were measured using colorimetry. Histopathological evaluations were assessed for cardiac damage and fibrosis by H&E and Masson's trichrome staining. Tramadol significantly decreased SOD and GPX activities and increased MDA levels compared with the CTL group. Both HIIT and MPH, either alone or in combination, were associated with a significant increase in SOD and GPX and a reduction of MDA levels. Both HIIT and MPH partially repaired the tramadol-induced changes in mRNA expression of DRP-1, and PINK-1. In addition, HIIT, MPH, and their combination significantly reversed histopathological changes associated with long-term tramadol use. These findings suggested that tramadol administration associated with a significant increase in oxidative stress parameters and cardiac damage in heart tissues of rats, which could be ameliorated by HIIT, MPH alone, or their combination.