Exercise Training Ameliorates The Tramadol-Induced Toxicity on VEGF/VEGFRs/PI3K/AKT Signaling Pathway in Testicular Tissue after Tramadol Withdrawal.

Background: The study investigated how exercise training protocols (ETPs) with different intensities can ameliorate the tramadol (TRA)-induced toxicity in the testicular tissue by upregulating VEGF/VEGFRs/PI3K/AKT signaling pathway in the post-withdrawal period. Materials and Methods: In this experimental study, thirty-six mature Wistar rats were included in two groups: one being a sedentary control group, and the other receiving TRA treatment (40 mg/kg, daily, ip). After 60 days, six rats from the TRA-received group were excluded (TRA-sole; euthanized after 60 days). The TRA administration was stopped and the rats were further divided into four subgroups: TRA/withdrawal (TRA/W), low (LICT), moderate (MICT), and high (HICT)-intensity continuous exercise training-received groups (n=6/each group). The expression levels of phosphoinositide 3-kinases (PI3K), protein Kinase B (AKT), vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGF R1) and 2 (VEGF R2) were assessed. Results: The expression levels of PI3K, AKT, VEGF, VEGF R1, and VEGF R2 were decreased in the TRA-sole group. No significant alterations were noted in the PI3K, AKT, VEGF, and VEGF R1 expressions after 60 days of withdrawal compared to the TRA-sole rats. However, this situation was reversed and the expression levels of PI3K, AKT, VEGF, VEGF R1, and VEGF R2 increased in the MICT and HICT-received groups. Conclusion: TRA disrupts the PI3K/AKT interaction, and this disruption is not easily reversed shortly after withdrawal. However, ETPs exert positive effects on PI3K/AKT signaling by promoting the expression of VEGF, VEGFR1, and R2. These results highlight the potential of ETPs to ameliorate the adverse effects of TRA on VEGF/VEGF R1, R2/PI3K/AKT signaling, even a short time after withdrawal.