The ascending cutaneous transmission through the middle cuneate nucleus is subject to cortico-feedback modulation. This work aimed to study the intracuneate cellular mechanisms underlying the cortico-cuneate influence. Single unit extracellular records combined with iontophoresis showed that the cortico-cuneate input activates cuneo-lemniscal (CL) and non-cuneo-lemniscal (nCL) cells via non-NMDA and NMDA receptors as shown by the decrease of the cortical-induced activation upon ejection of CNQX and APV, either alone or in combination. These results were confirmed by in vivo intracellular recordings. Two subgroups of nCL cells were distinguished according to their sensitivity to iontophoretic ejection of glycine and its antagonist, strychnine. Finally, the cortical-evoked activation of CL cells was decreased by GABA and increased by glycine acting at a strychnine-sensitive site, indicating that glycine indirectly affects the cuneolemniscal transmission. A model is proposed whereby the cortex influences CL cells through three different mechanisms, producing: i) activation via non-NMDA and NMDA receptors, ii) inhibition through GABAergic nCLs, and iii) disinhibition via serial glycinergic-GABAergic nCL cells. These cortico-cuneate feedback effects serve to potentiate the activity of CL cells topographically aligned through direct activation and disinhibition, while inhibiting, via GABAergic cells, other CL neurons not topographically aligned.