Motor cortex stimulation (MCS) is used as a therapy for patients with refractory neuropathic pain. Experimental evidence suggests that the motor cortex (MC) is involved in the modulation of normal nociceptive response, but the underlying mechanisms have not been clarified yet. In previous studies, we demonstrated that MCS increases the nociceptive threshold of naive conscious rats by inhibiting thalamic sensory neurons and disinhibiting the neurons in periaqueductal gray (PAG), with the involvement of the opioid system. The aim of this study was to investigate the possible somatotopy of the motor cortex on MCS-induced antinociception and the pattern of neuronal activation evaluated by Fos and Egr-1 immunolabel in an attempt to better understand the relation between MC and analgesia. Rats received epidural electrode implants placed over the MC, in three distinct areas (forelimb, hindlimb or tail), according to a functional mapping established in previous studies. Nociceptive threshold was evaluated under 15-min electrical stimulating sessions. MCS induced selective antinociception in the limb related to the stimulated cortex, with no changes in other evaluated areas. MCS decreased Fos immunoreactivity (Fos-IR) in the superficial layers of the dorsal horn of the spinal cord for all evaluated groups and increased Fos-IR in the PAG, although no changes were observed in the PAG for the tail group. Egr-1 results were similar to those obtained for Fos. Data shown herein demonstrate that MCS elicits a substantial and selective antinociceptive effect, which is mediated, at least in part, by the activation of descendent inhibitory pain pathway.