Although the clinical benefits of SCS are clear and its success rate remains high, the mechanisms have not been completely understood. Melzack and Wall in 1965 suggested gate-control theory that SCS stimulates the afferent fibers of the dorsal column by closing the gate of pain transmission to reduce pain [1]. But there is little evidence that SCS influences nociceptive pain.

The mechanisms of action may differ depending on the type of pain targeted for treatment. For example, its effect on neuropathic pain may be secondary to stimulation-induced suppression of central excitability, whereas the beneficial effect of SCS on ischemic pain may be related to stimulation-induced inhibition of sympathetic nervous system influences and antidromic vasodilation, which increases blood flow and reduces oxygen demand [4]. Until now, two theories can explain the effects of SCS. One is the antidromic mechanism which states that, at the spinal L2-5 segments, SCS activates interneurons containing extracellular signal-regulated kinase (ERK), protein kinase B (AKT), and possibly other intracellular signaling molecules, and subsequently stimulates the spinal terminals of transient receptor potential vanilloid receptor-1 (TRPV1) containing sensory fibers. The neural information is transmitted from the site of stimulation in the spinal segments to the nerve endings in the peripheral tissues and results in the production and release of vasodilators, including calcitonin gene-related peptide (CGRP). CGRP, as the most powerful vasodilator, leads to SCS-induced vasodilation directly. And the subsequent release of nitric oxide may be associated with vascular smooth muscle relaxation and peripheral blood flow increase in response to SCS. Another theory is that SCS induces decreased sympathetic efferent activity and subsequently reduces vasoconstriction and enhances blood flow in the lower limbs and feet. This is called the sympathetic mechanism. The two mechanisms are complementary, and the balance between them is affected by tonic sympathetic activity, SCS intensity, and individual patients or animal strains [5–8].