# Phox2a in Lateral Spinal Nucleus Tac1‐Positive Neurons Mediates Histamine‐Independent Acute Itch

## TL;DR

This study identifies Phox2a in specific spinal neurons as a key regulator of non-histamine-related itch and suggests it could be a new treatment target.

## Contribution

Phox2a in Tac1+ lateral spinal nucleus neurons is newly identified as a selective regulator of histamine-independent itch.

## Key findings

- LSNTac1 neurons are specifically activated during histamine-independent itch caused by chloroquine.
- Phox2a overexpression in LSNTac1 neurons reduces itch behavior and decreases excitatory synaptic current amplitude.
- Phox2a is downregulated in LSNTac1 neurons during chloroquine-induced itch.

## Abstract

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.

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 LSNTac1 neurons and Phox2a in itch modulation.

LSNTac1 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 LSNTac1 neurons, was downregulated during CQ‐induced itch. Overexpression of Phox2a in LSNTac1 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.

Our findings identify Phox2a in LSNTac1 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.

Phox2a expression in LSNTac1 neurons is selectively reduced in chloroquine‐induced itch. Overexpression of Phox2a alleviates this itch by the amplitude of spontaneous excitatory postsynaptic currents, revealing a potential treatment target for histamine‐independent pruritus.