Long non-coding RNA Carip loss alters parabrachial synapses and drives pain hypersensitivity

Pain is an unpleasant sensory and emotional experience that can lead to anxiety and attention deficit. Hitherto, effective therapies for pain remain limited. Although multiple factors were reported to modulate the pain, few studies have explored the neural mechanisms of long non-coding RNA (lncRNA) in pain. Here, we identified a high expression level of Carip in the lateral parabrachial nucleus (LPBN), which participates in modulating pain-like behaviors. Thermal stimulation can induce the significant upregulation of lncRNA Carip in the LPBN neurons. The knock-out (KO) of Carip elevates pain thresholds. Electrophysiological assays in LPBN→CeA neurocircuit demonstrated that Carip KO simultaneously increased the amplitude of evoked AMPAR excitatory postsynaptic currents (eEPSCs) and evoked GABAAR inhibitory postsynaptic currents (eIPSCs), disrupting of the neuronal excitation and inhibition (E/I) balance due to the enhanced phosphorylation of synapsin1 Ser9 via protein kinase A dependent signaling cascade in LPBN neurons, which is deemed as the crucial reason for abnormal pain-like behaviors. Importantly, blocking the Carip-mediated intracellular signaling cascade by specific knockdown of synapsin1 (synapsin1 KD) or PKA (PKA KD) in LPBN neurons of Carip KO mice not only restores the E/I balance but also ameliorates the abnormal pain-like behaviors. Together, our study demonstrates the important roles of Carip in pain-like behaviors, and suggests that modulating E/I balance by Carip-mediated intracellular signaling pathway could effectively alleviate pain. Our studies provide the synaptic and molecular explanations of how Carip modulates pain-like behaviors.