<p>The pain induced by the friction between residual limb and prosthetic socket is the significant issue that influence the comfort of prostheses. In this study, to reveal and compare the pain generation and processing mechanisms in amputees and healthy individuals, the skin friction, electroencephalogram, and functional Near-Infrared Spectroscopy tests were carried out. The Hodgkin-Huxley and Gate Control Theory models were used to reveal the neural transduction and transmission of frictional pain and connect the surface friction and brain activation of pain. The skin friction and subjective evaluation tests showed that compared with healthy skin, the residual limb skin exhibited poorer elastic properties, lower friction coefficients and higher frictional pain thresholds. The results showed that the hemodynamic response of amputees was insignificant and brain regions of amputees related with <i>γ</i> oscillations was smaller compared with healthy individuals. The changes of skin mechanical properties and neural reorganization may responsible for the difference in frictional pain response between amputees and healthy individuals. The results also showed that the increasing intensity of frictional pain can induce the increase of T-cell potential, resulting in the increasing HbO concentration and <i>γ</i> oscillations. This study provides a better understanding of pain generation mechanisms from skin surface to brain response using mathematical models. It also reveals the differences in frictional pain between amputees and healthy individuals.</p>