A subset of spinal dorsal horn interneurons crucial for gating touch-evoked pain-like behavior

Abstract

A cardinal, intractable symptom of neuropathic pain is mechanical allodynia, pain caused by innocuous stimuli via low-threshold mechanoreceptors such as Aβ fibers. However, the mechanism by which Aβ 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 Aβ fiber-derived signals to morphine-resistant pain-like behavioral responses. AAV-NpyP+ neurons received excitatory inputs from Aβ 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 Aβ fibers was impaired. Conversely, chemogenetic activation of AAV-NpyP+ neurons in nerve-injured rats reversed Aβ 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 Aβ fiber signals into pain-like behavioral responses. Thus, enhancing activity of these neurons may offer a novel strategy for treating neuropathic allodynia.

A harmonized atlas of mouse spinal cord cell types and their spatial organization

“…The Npy dorsal, the inhibitory family was comprised of Inhib-12 and Inhib-13. Studies suggest this family's markers identify neurons involved in mechanical itch and pain 73,78,79 . These clusters expressed Npy and were distinguished by low levels of Vgf (Inhib-12) or by expression of Qrfpr (Inhib-13).…”

A Role for Superficial Heat Therapy in the Management of Non-Specific, Mild-to-Moderate Low Back Pain in Current Clinical Practice: A Narrative Review

“…Neurotransmitters elicit changes in the interneurons of the spinal dorsal horns that influence their permeability, switching, and guidance mechanisms, which, in turn, affects the way they relay stimuli (including pain) [ 23 , 24 , 25 , 26 , 27 ]. Depending on their location and the cause of the activation of the pain receptors, there may be a local increase in the tone of the segmentally assigned muscles, with the formation of trigger points.…”

GABAergic Mechanisms Can Redress the Tilted Balance between Excitation and Inhibition in Damaged Spinal Networks

“…Based on the expression of transcription factors, different subtypes of spinal interneuron with distinct settling positions, neurotransmitter expression, and profiles of connectivity have been identified [ 70 ], among which a few have an inhibitory phenotype [ 9 ]. In particular, an adenovirus vector including a neuropeptide Y promoter has been recently used to discover, in the superficial dorsal horn, a subset of inhibitory GABAergic interneurons (AAV-NpyP) with the ability to prevent the conversion of touch-sensing signals into pain-like behavioral responses [ 71 ]. This class of interneuron receives mono- or polysynaptic excitatory inputs from touch-sensing fibers and uses GABA for transmitting inhibitory signals to lamina I neurons that project to the brain, thus avoiding abnormal excitation following innocuous mechanical stimulations (Fig.…”