Transthyretin-mediated regulation of neuropathic pain and anxiety-like behavior in the lateral parabrachial nucleus.

Neuropathic pain presents a complex challenge in clinical treatment due to its multifaceted etiology and frequent comorbidities with anxiety. Despite its prevalence, the underlying molecular, cellular, and circuit mechanisms remain poorly understood. The lateral parabrachial nucleus (LPBN) is a critical center that regulates both pain perception and the emotional aspects. In this study, single-cell sequencing shows upregulated transthyretin (TTR) in neuropathic pain models. Through bidirectional conditional knockout (cKO) and overexpression of TTR in LPBN neurons of mice, we confirm that TTR in LPBN glutamatergic neurons serves as a necessary and sufficient regulator of pain-anxiety comorbidity. Furthermore, TTR plays a pivotal role in pain regulation by binding to its receptor, receptor for advanced glycation end products (RAGE), thereby influencing neuroinflammation and neuronal excitability through the NF-κB signaling pathway. These results highlight potential molecular targets for the treatment of neuropathic pain.