In 1957, Frank & Fuortes described a new mechanism for the regulation of the synaptic effectiveness of sensory fibres in the vertebrate spinal cord, namely presynaptic inhibition. However, it was not until the early sixties that Eccles and his collaborators related this inhibition to primary afferent depolarization (PAD; for review see Rudomin & Schmidt, 1999).

It is now fairly well established, from both electrophysiological and morphological investigations, that the terminal arborizations of large cutaneous and muscle afferents in the vertebrate spinal cord are the targets of specific sets of GABAergic interneurones. Activation of GABAA receptors in the subsynaptic regions of the afferent terminals increases their permeability to chloride ions and produces PAD. Presynaptic inhibition would result from the depolarization produced by the outward chloride currents, as well as from increased membrane conductance, which may reduce, or prevent, conduction of action potentials at branch points within the intraspinal arborizations. There is in addition activation of GABAB receptors, which also reduces synaptic effectiveness without producing PAD (for review see Willis, 1998; Rudomin & Schmidt, 1999).