A Subset Of Spinal Dorsal Horn Interneurons Crucial For Gating Touch-Evoked Pain-Like Behavior

A cardinal, intractable symptom of neuropathic pain is mechanical allodynia, pain caused by innocuous stimuli via low-threshold mechanoreceptors such as A beta fibers. However, the mechanism by which A beta fiber-derived signals are converted to pain remains incompletely understood. Here we identify a subset of inhibitory interneurons in the spinal dorsal horn (SDH) operated by adeno-associated viral vectors incorporating a neuropeptide Y promoter (AAV-NpyP(+)) and show that specific ablation or silencing of AAV-NpyP(+) SDH interneurons converted touch-sensing A beta fiber-derived signals to morphine-resistant pain-like behavioral responses. AAV-NpyP(+) neurons received excitatory inputs from A beta fibers and transmitted inhibitory GABA signals to lamina I neurons projecting to the brain. In a model of neuropathic pain developed by peripheral nerve injury, AAV-NpyP(+) neurons exhibited deeper resting membrane potentials, and their excitation by A beta fibers was impaired. Conversely, chemogenetic activation of AAV-NpyP(+) neurons in nerve-injured rats reversed A beta fiber-derived neuropathic pain-like behavior that was shown to be morphine-resistant and reduced pathological neuronal activation of superficial SDH including lamina I. These findings suggest that identified inhibitory SDH interneurons that act as a critical brake on conversion of touch-sensing A beta fiber signals into pain-like behavioral responses. Thus, enhancing activity of these neurons may offer a novel strategy for treating neuropathic allodynia.