Primary afferent neurotransmission is the fundamental first step in the central processing of sensory stimuli. It is controlled by pre- and post-synaptic inhibitory mechanisms. Presynaptic inhibition (PSI) is “more powerful than postsynaptic inhibition in depressing the central excitatory actions of almost all primary afferent fibers”[Eccles] and is the reason why you can't tickle yourself. A major mechanism producing afferent PSI is via a counterintuitive channel-mediated depolarization of their intraspinal terminals which conveniently can be recorded as a dorsal root potential (DRP) (fig 1).

Based on measures of DRP latency and drug actions, it has been assumed though never directly demonstrated; that this primary afferent depolarization (PAD) of touch and movement-encoding low-threshold afferents is mediated by a minimally trisynaptic pathway, and that GABAergic interneurons are essential (fig 2).

We have evidence suggesting that much of this afferent stimulation-evoked PADis instead generated by more direct synaptic pathways, that may be: (i) independent of classical GABAA receptors and (ii) independent of GABA. Putative novel mechanisms are shown in fig 3.

A mechanistic proof of these assertions involves a coalescence of pioneering electrophysiological studies in the in vitro nerves-attached mouse spinal cord with essential pharmacological, molecular and biophysical characterizations of the transmitter(s) released & ionotropic receptor subunits expressed in primary afferents.