The locus coeruleus modulates acute itch via ERK-dependent neuronal excitability

The locus coeruleus (LC), as the primary noradrenergic nucleus in the brain, plays a pivotal role in sensory modulation and stress responses. However, its specific involvement in acute itch remains incompletely understood. In this study, we established acute itch models by intradermal injection of Compound 48/80 (C48/80) and chloroquine (CQ) into the neck region of mice. Both stimuli significantly increased c-Fos expression in the bilateral LC. Electrophysiological recordings from LC neurons in C48/80- or CQ-treated mice revealed enhanced excitability under ramp stimulation, manifesting as increased spike numbers, shorter initial spike latency, and a reduced adaptation index compared to saline-treated controls. During step-current stimulation, the same neurons exhibited a significantly lower rheobase and higher firing frequency, despite unaltered resting membrane potential and action potential threshold. Moreover, C48/80-induced acute itch markedly upregulated phosphorylated ERK (pERK) expression in the LC. Microinjection of the ERK pathway inhibitor PD98059 into the LC reduced pERK levels and significantly attenuated scratching behaviors induced by both C48/80 and CQ. Electrophysiologically, PD98059-treated neurons displayed decreased firing numbers, prolonged initial spike latency, and increased adaptation index during ramp stimulation. Under step-current stimulation, these neurons showed elevated rheobase and reduced spiking. These results establish a causal role of the ERK pathway in the LC in the regulation of neuronal excitability and acute itch, providing a mechanistic foundation for future therapeutic exploration.