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Addiction is a serious public health problem, and the current pharmacotherapy is unable to prevent drug use reinstatement. Studies have focused on physical exercise as a promising coadjuvant treatment. Our research group recently showed beneficial neuroadaptations in the dopaminergic system related to amphetamine-relapse prevention involving physical exercise-induced endogenous opioid system activation (EXE-OS activation). In this context, additional mechanisms were explored to understand the exercise benefits on drug addiction. Male rats previously exposed to amphetamine (AMPH, 4.0 mg/kg) for 8 days were submitted to physical exercise for 5 weeks. EXE-OS activation was blocked by naloxone administration (0.3 mg/kg) 5 min before each physical exercise session. After the exercise protocol, the rats were re-exposed to AMPH for 3 days, and in sequence, euthanasia was performed and the VTA and NAc were dissected. In the VTA, our findings showed increased immunocontent of proBDNF, BDNF, and GDNF and decreased levels of AMPH-induced TrkB; therefore, EXE-OS activation increased all these markers and naloxone administration prevented this exercise-induced effect. In the NAc, the same molecular markers were also increased by AMPH and decreased by EXE-OS activation. In this study, we propose a close relation between EXE-OS activation beneficial influence and a consequent neuroadaptation on neurotrophins and dopaminergic system levels in the mesolimbic brain area, preventing the observed AMPH-relapse behavior. Our outcomes bring additional knowledge concerning addiction neurobiology understanding and show that EXE-OS activation may be a potential adjuvant tool in drug addiction therapy. [ABSTRACT FROM AUTHOR]