Abstract
Histamine-dependent and -independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded by Npr1. However, BNP also binds to its cognate receptor, NPRC encoded by Npr3 with equal potency. Moreover, natriuretic peptides (NP) signal through the Gi-couped inhibitory cGMP pathway that is supposed to inhibit neuronal activity, raising the question of how BNP may transmit itch information. Here, we report that Npr3 expression in laminae I-II of the dorsal horn partially overlaps with NMB receptor (NMBR) that transmits histaminergic itch via Gq-couped PLCβ-Ca2+ signaling pathway. Functional studies indicate that NPRC is required for itch evoked by histamine but not chloroquine (CQ), a nonhistaminergic pruritogen. Importantly, BNP significantly facilitates scratching behaviors mediated by NMB, but not GRP. Consistently, BNP evoked Ca2+ responses in NMBR/NPRC HEK 293 cells and NMBR/NPRC dorsal horn neurons. These results reveal a previously unknown mechanism by which BNP facilitates NMB-encoded itch through a novel NPRC-NMBR cross-signaling in mice. Our studies uncover distinct modes of action for neuropeptides in transmission and modulation of itch in mice.
Highlights
51 How itch and pain information is encoded and transmitted has been subjected to numerous studies for more than a century(Chen, 2021)
Considering that the guanylyl cyclase (GC)-cGMP signal 87 transduction pathway mediated by brain natriuretic peptide (BNP) is inhibitory(Potter et al, 2006) and that BNP88 NPRA/NPRC signaling may exert an inhibitory rather than excitatory function, analogous to G I protein-coupled signaling, it is paradoxical that BNP would transmit rather than inhibiting itch information. 92 In the present study, we have examined these open questions using a combination of RNA93 scope ISH, genetic knockout (KO) mice, spinal siRNA knockdown, cell ablation, calcium 94 imaging, pharmacological and optogenetic approaches
BNP-facilitated histamine itch was markedly reduced by U 73122 treatment, a selective PLC inhibitor (Figure 3I), suggesting an intracellular coupling between NPRC and NMB receptor (NMBR). 227 We previously showed that neuromedin B (NMB) exerts its role exclusively through NMBR in the spinal cord, as NMB is a functional antagonist for GRPR in spite of its cross-binding activity with GRPR in the spinal cord (Zhao et al, 2014b)
Summary
51 How itch and pain information is encoded and transmitted has been subjected to numerous studies for more than a century(Chen, 2021). Murine GRP-GRPR signaling is important for the development of contact dermatitis-induced itch (Chen et al, 2020; Liu et al, 2020; Shiratori-Hayashi et al, 2015; Zhao et al, 2013). These findings are in accordance with human and animal studies showing that histaminergic and nonhistaminergic itch is transmitted through parallel primary afferent pathways (Chen, 2021; Johanek et al, 2007; Namer et al, 2008; Roberson et al, 2013; Wilson et al, 2011). Our studies confirmed that BNP is an inhibitory neuropeptide that alone fails to evoke Ca2+ response and itch-related scratching behavior, in contrast to GRP and NMB; BNP becomes excitatory by facilitating NMB99 mediated itch transmission. . distinct modes of action for neuropeptides coordinate itch transmission in the spinal cord
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