<p>Physical inactivity or sedentary lifestyle is recognized as a risk factor for many diseases including cardiovascular disease, diabetes, cancer, depression, dementia and chronic pain, whereas physical exercise such as running, swimming and cycling is approved as an effective non–pharmacological intervention to improve pain. Many clinical and animal studies demonstrated that physical exercise sig­nificantly improves pain–related behaviors such as mechanical allodynia and heat hyperalgesia (exercise–induced hypoalgesia: EIH). Furthermore, multiple events including marked alterations in cytokines, neurotrophins, neurotransmitters and endogenous opioids in injured peripheral nerves, dorsal root ganglia, spinal dorsal horns and the brainstem following physical exercise have been proposed as potential mechanisms of EIH effects. On the other hand, neuroimaging analysis in chronic pain patients demonstrated that dysfunction of the mesocortico–limbic system including the ventral tegmental area (VTA), amygdala (Amyg), hippocampus (Hipp), nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) plays critical roles in the development and maintenance of chronic pain, which provided an important clue to elucidate novel mechanisms underlying EIH effects. Voluntary exercise (VE) in neuropathic pain (NPP) model mice significantly improved pain behaviors of these mice, and significant positive–correlation was observed between their total running distances and pain thresholds, suggesting that the increase of physical activity enhances analgesic levels. VE in NPP model mice significantly activated dopamine neurons in the lateral VTA, GABA neurons in the NAc lateral shell, glutamate (Glu) neurons in the medial basal Amyg and the deep layers of mPFC, whereas GABA neurons in the central nucleus of Amyg, Glu neurons in the lateral basal Amyg and GABA neurons in the superficial layers of mPFC were inhibited by VE. These changes may promote functional restoration of the mesocortico–limbic system leading to hypoalgesia and euphoria. Thus, the present review has shed light on the role of mesocortico–limbic system in the mechanisms underlying the EIH effects.</p>