Spinal Cord Stimulation Attenuates Itch-Like Behavior and Dermatitis: Contribution of a Spinal Inhibitory Neuronal Ensemble and Associated Reductions in GRPR and Sympathetic Signaling.

Chronic inflammatory itch is sustained by reciprocal interactions among pruriceptive circuits, scratching-induced skin injury, immune-cell infiltration, and autonomic neuroimmune signaling. Spinal cord stimulation is known to reshape dorsal horn sensory processing, but whether it modulates neuroimmune inflammation during dermatitis-associated itch remains unclear. Using acute pruritogen-evoked itch and DNFB-induced chronic dermatitis models in mice, we examined the effects of low- and high-frequency spinal cord stimulation on itch-like behavior, skin inflammation, spinal GRPR-associated neuronal activation, and sympathetic-associated neuroimmune changes. Activity-dependent FosTRAP2 labeling combined with chemogenetic activation or inhibition was used to test the functional contribution of the HF-SCS/TRAP-defined neuronal ensemble. Spinal cord stimulation reduced pruritogen-evoked licking/biting and chronic DNFB-associated itch-like behavior, accompanied by decreased epidermal hyperplasia, T-cell infiltration, and IL-1β/TNF-α-associated inflammatory signals in lesional skin. HF-SCS increased c-Fos activity within a prominent Pax2+ inhibitory neuronal component in the dorsal horn. Chemogenetic reactivation of the HF-SCS/TRAP-defined neuronal ensemble recapitulated the behavioral and cutaneous effects associated with SCS, whereas chemogenetic inhibition impaired the protective efficacy of stimulation. Spinal cord stimulation was also associated with reduced GRPR-related neuronal activation and Grpr expression. Anatomical tracing indicated an association between the HF-SCS/TRAP-defined neuronal ensemble and ChAT+ sympathetic preganglionic neurons, while HF-SCS was accompanied by reduced sympathetic-associated markers in skin and the spinal intermediolateral region. These findings identify spinal cord stimulation as a preclinical neuromodulatory approach that attenuates dermatitis-associated itch and cutaneous neuroinflammation. The data support a functional contribution of the HF-SCS/TRAP-defined neuronal ensemble, which is enriched in Pax2+ inhibitory neurons, while the reductions in GRPR-related activity and sympathetic-associated signaling remain associative findings.