The mechanism of action of TENS has been widely investigated and involves local and systemic effects. In particular, experiments using animal models have shown systemic action trough involvement of the autonomic nervous system (ANS). Endogenous opioid and descending pain modulatory systems are thought to be involved in central activation during TENS stimulation. In particular, pain modulation occurs via endogenous opioids and affects the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) brain regions. The PAG provides a neuroanatomical and neuro-functional substrate to couple cortical outflow with the adequate autonomic response.