• High-intensity interval training (HIIT) and methylphenidate (alone and in combination) alleviates tramadol-induced cardiac side effects in male rats, potentially through the modulation of mitochondrial function
  • Sara Shirazpour,1 Gholamreza Sepehri,2 Farzaneh Rostamzadeh,3,* Homa Jafari,4 Maryam Iranpour,5
    1. Cardiovascular research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
    2. Cardiovascular research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
    3. Physiology research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
    4. Endocrinology and Metabolism research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences Kerman, Iran
    5. Department of Pathology, Pathology and Stem Cell research Center, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.


  • Introduction: Tramadol, a commonly prescribed analgesic for moderate to severe pain, has been linked to considerable cardiovascular risks. This study aimed to examine the effects of high-intensity interval training (HIIT) and methylphenidate (MPH), alone and in combination on mitochondrial quality in the cardiac tissue of male Wistar rats subjected to prolonged tramadol administration.
  • Methods: Fifty-six male Wistar rats (220–250 g) were randomly assigned to seven experimental groups: control (CTL), MPH, tramadol (TR), HIIT, MPH+HIIT, TR+HIIT, and MPH+TR+HIIT. Tramadol was administered via intraperitoneal injection at a dose of 50 mg/kg/day, five days per week during the first month and three days per week during the second month. MPH was administered at a dose of 10 mg/kg, three days per week for two months. Rats in the relevant groups underwent HIIT five days per week for eight weeks. Cardiac mRNA expression levels of MFN-2, DRP-1, PINK-1, and Parkin were quantified using real-time PCR.
  • Results: Tramadol and methylphenidate alone had no effect on MFN-2 expression, whereas the combination of MPH and TR increased MFN-2 mRNA expression compared to the CTL and TR groups (P < 0.05). MFN-2 mRNA expression was higher in the group receiving the combination of HIIT, MPH, and TR than TR and CTL groups alone (P < 0.01). In addition, DRP-1 mRNA expression increased in the group receiving tramadol compared to the CTL group (P < 0.001). Its expression was decreased by MPH and HIIT (P < 0.001). However, DRP-1 mRNA expression was still higher than that in the CTL group (P < 0.01). DRP-1 mRNA expression was higher in the TR+MPH and TR+MPH+HIIT groups than in the MPH group (P < 0.001). PINK-1 mRNA expression was significantly higher in the group that receiving tramadol compared to the CTL group (P < 0.01). HIIT, MPH, and MPH+HIIT decreased PINK-1 mRNA expression in rats receiving tramadol (P < 0.05 to P < 0.001). Parkin mRNA expression was higher in TR+MPH and TR+MPH+HIIT groups than in the CTL, MPH, and, TR groups (P < 0.05 to P < 0.001).
  • Conclusion: The findings of this study underscore the potential adverse effects of tramadol on cardiac health, primarily mediated by mitochondrial dysfunction. Notably, both HIIT and MPH were effective in mitigating tramadol-induced cardiac impairments by enhancing mitochondrial dynamics. These results highlight the therapeutic value of exercise interventions in managing drug-induced cardiotoxicity and emphasize the role of mitochondrial quality control in cardiac protection.
  • Keywords: Tramadol, Methylphenidate, Exercise, DRP-1, PINK-1