Phox2a in Lateral Spinal Nucleus Tac1-Positive Neurons Mediates Histamine-Independent Acute Itch.

AIMS: While acute itch comprises histamine-dependent and -independent subtypes, critical mechanisms underlying histamine-independent itch remain poorly understood. This study investigates the role of paired-like homeobox 2a (Phox2a) in tachykinin 1-positive (Tac1(+)) neurons of the lateral spinal nucleus (LSN) as a novel target for histamine-independent pruritus intervention. METHODS: We combined chemogenetic manipulation (viral-mediated neuronal activation/inhibition), whole-cell patch-clamp recordings, immunohistochemistry, fluorescence in situ hybridization, Western blotting, and behavioral assays to investigate the role of LSN(Tac1) neurons and Phox2a in itch modulation. RESULTS: LSN(Tac1) neurons were specifically activated during chloroquine (CQ)-induced histamine-independent itch. Chemogenetic activation of these neurons exacerbated scratching, whereas inhibition suppressed itch behavior. Notably, Phox2a, expressed in LSN(Tac1) neurons, was downregulated during CQ-induced itch. Overexpression of Phox2a in LSN(Tac1) neurons significantly alleviated CQ-evoked scratching and was accompanied by a reduction in spontaneous excitatory postsynaptic currents (sEPSCs) amplitude without a change in sEPSCs frequency. CONCLUSIONS: Our findings identify Phox2a in LSN(Tac1) neurons as a selective regulator of histamine-independent acute itch through presynaptic excitability. This highlights Phox2a as a novel therapeutic target for histamine-independent pruritus intervention.