Defining a Spinal Microcircuit that Gates Myelinated Afferent Input: Implications for Tactile Allodynia

Chronic pain presents a major unmet clinical problem. One of the most common symptoms of chronic pain is tactile allodynia, where previously innocuous mechanical stimuli are perceived as painful. To help develop more effective analgesics to treat this condition, a better understanding of the neuronal circuits underlying sensory perception in necessary. We have shown that inhibitory interneurons in the spinal dorsal horn that express parvalbumin (PV) form axoaxonic synapses on to the central terminals of low threshold mechanoreceptive (LTMR) afferents. Here, we define a spinal microcircuit comprising of LTMR afferents, inhibitory PV interneurons, and glutamatergic vertical cells whose axons project to lamina I, that explains how LTMR input can activate pain circuits under pathological conditions. We show that these PV cells receive monosynaptic input from myelinated LTMR afferents from both hairy and glabrous skin. We also determine that these interneurons are the source of axoaxonic synapses on to the central terminals of LTMR afferents that appose vertical cells, forming triadic synaptic arrangements. Furthermore, we provide evidence that these interneurons generate both GABAergic presynaptic inhibition of myelinated LTMR afferents, and postsynaptic inhibition of vertical cells through the release of GABA and glycine. In neuropathic mice, PV cell excitability is reduced, but we find no evidence of structural plasticity. Taken together, these findings show that PV cell-mediated presynaptic inhibition of LTMR afferents and postsynaptic inhibition of vertical cells both play critical roles in the normal perception of mechanical stimuli, and identify this microcircuit as a target for therapeutic intervention to alleviate allodynia.