Chemogenetic silencing of spinal cord-projecting cortical neurons attenuates Aß fiber-derived neuropathic allodynia in mice.

Mechanical allodynia (pain caused by innocuous mechanical stimulation) is a hallmark symptom of neuropathic pain occurring following peripheral nerve injury (PNI). Using a transgenic mouse line, in which myelinated primary afferents, including Aß fibers, express channelrhodopsin-2, we found that illumination of the plantar skin of mice following PNI produced an Aß fiber-mediated pain-like withdrawal behavior and increased c-FOS+ neurons in the superficial spinal dorsal horn (SDH). These two responses were attenuated by chemogenetic silencing of primary sensory cortex (S1) neurons projecting directly to the SDH. These findings indicate that spinally projecting cortical S1 neurons contribute to Aß fiber-derived neuropathic allodynia.

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 Aß fibers. However, the mechanism by which Aß 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 Aß fiber-derived signals to morphine-resistant pain-like behavioral responses. AAV-NpyP+ neurons received excitatory inputs from Aß 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 Aß fibers was impaired. Conversely, chemogenetic activation of AAV-NpyP+ neurons in nerve-injured rats reversed Aß 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 Aß fiber signals into pain-like behavioral responses. Thus, enhancing activity of these neurons may offer a novel strategy for treating neuropathic allodynia.