Timing Mechanisms Underlying Gate Control by Feedforward Inhibition

The gate control theory proposes that A beta mechanoreceptor inputs to spinal pain transmission T neurons are gated via feedforward inhibition, but it remains unclear how monosynaptic excitation is gated by disynaptic inhibitory inputs that arrive later. Here we report that A beta-evoked, non-NMDAR-dependent EPSPs in T neurons are subthreshold, allowing time for inhibitory inputs to prevent action potential firing that requires slow-onset NMDAR activation. Potassium channel activities-including I-A, whose sizes are established constitutively by Preprodynorphin(Cre)-derived inhibitory neurons-either completely filter away A beta inputs or make them subthreshold, thereby creating a permissive condition to achieve gate control. Capsaicin-activated nociceptor inputs reduce I-A and sensitize the T neurons, allowing Ab inputs to cause firing before inhibitory inputs arrive. Thus, distinct kinetics of glutamate receptors and electric filtering by potassium channels solve the timing problem underlying the gating by feedforward inhibition, and their modulation offers a way to bypass the gate control.