Sodium Leak Channel in Glutamatergic Neurons of the Lateral Parabrachial Nucleus Modulates Inflammatory Pain in Mice

Abstract

Elevated excitability of glutamatergic neurons in the lateral parabrachial nucleus (PBL) is associated with the pathogenesis of inflammatory pain, but the underlying molecular mechanisms are not fully understood. Sodium leak channel (NALCN) is widely expressed in the central nervous system and regulates neuronal excitability. In this study, chemogenetic manipulation was used to explore the association between the activity of PBL glutamatergic neurons and pain thresholds. Complete Freund’s adjuvant (CFA) was used to construct an inflammatory pain model in mice. Pain behaviour was tested using von Frey filaments and Hargreaves tests. Local field potential (LFP) was used to record the activity of PBL glutamatergic neurons. Gene knockdown techniques were used to investigate the role of NALCN in inflammatory pain. We further explored the downstream projections of PBL using cis-trans-synaptic tracer virus. The results showed that chemogenetic inhibition of PBL glutamatergic neurons increased pain thresholds in mice, whereas chemogenetic activation produced the opposite results. CFA plantar modelling increased the number of C-Fos protein and NALCN expression in PBL glutamatergic neurons. Knockdown of NALCN in PBL glutamatergic neurons alleviated CFA-induced pain. CFA injection induced C-Fos protein expression in central nucleus amygdala (CeA) neurons, which was suppressed by NALCN knockdown in PBL glutamatergic neurons. Therefore, elevated expression of NALCN in PBL glutamatergic neurons contributes to the development of inflammatory pain via PBL-CeA projections.

Role of sodium leak channel (NALCN) in sensation and pain: an overview

“…In addition to the DRG and spinal cord, the NALCN in the brain was also found to be related to the regulation of pain. Wu et al showed that knocking down NALCN in lateral parabrachial nucleus (PBL) glutamatergic neurons alleviated CFA-induced pain in mice ( Wu et al, 2023 ). Their findings further suggested that the NALCN in PBL glutamatergic neurons regulates inflammatory pain via PBL-central nucleus amygdala (CeA) projections.…”

“…Current evidence from both in vivo and in vitro experiments indicates that NALCN plays a pivotal role in controlling pain ( Eigenbrod et al, 2019 ; Zhang et al, 2021 ; Li et al, 2021 ; Wu et al, 2023 ). A previous study also indicated that the NALCN determines the intrinsic excitability of spinal projection neurons using in vitro experiments ( Ford et al, 2018 ), which suggests that the NALCN contributes to sensory conduction and pain perception.…”

“…According to the results of recent studies, the role of the NALCN in pain and sensation in peripheral DRG and spinal cord neurons ( Ford et al, 2018 ; Eigenbrod et al, 2019 ; Zhang et al, 2021 ; Li et al, 2021 ; Tian et al, 2023 ) appears to be more important than that in brain neurons ( Wu et al, 2023 ). However, NALCN may be associated with central sensitization induced by chronic pain because NALCN is widely expressed in the central nervous system and controls neuronal excitability ( Lu et al, 2007 ; Ren, 2011 ).…”

“…Recent studies have shown that NALCN is also abundant in the spinal cord and dorsal root ganglion (DRG) of rodents ( Zhang et al, 2021 ; Li et al, 2021 ), indicating that NALCN might be implicated in important animal behaviors, such as pain and sensation. Increasing in vitro and/or in vivo evidence has shown that NALCN is associated with physiological sensation or pain ( Figure 1 ) ( Ford et al, 2018 ; Eigenbrod et al, 2019 ; Saro et al, 2020 ; Zhang et al, 2021 ; Li et al, 2021 ; Tian et al, 2023 ; Wu et al, 2023 ). Here, we will review the current literature to summarize the contribution of the NALCN to sensation and pain.…”