B-Type Natriuretic Peptide is Neither Itch-Specific Nor Functions Upstream of the GRP-GRPR Signaling Pathway

Abstract

BackgroundA recent study by Mishra and Hoon identified B-type natriuretic peptide (BNP) as an important peptide for itch transmission and proposed that BNP activates spinal natriuretic peptide receptor-A (NPRA) expressing neurons, which release gastrin releasing peptide (GRP) to activate GRP receptor (GRPR) expressing neurons to relay itch information from the periphery to the brain (Science 340:968–971, 2013). A central premise for the validity of this novel pathway is the absence of GRP in the dorsal root ganglion (DRG) neurons. To this end, they showed that Grp mRNA in DRG neurons is either absent or barely detectable and claimed that BNP but not GRP is a major neurotransmitter for itch in pruriceptors. They showed that NPRA immunostaining is perfectly co-localized with Grp-eGFP in the spinal cord, and a few acute pain behaviors in Nppb -/- mice were tested. They claimed that BNP is an itch-selective peptide that acts as the first station of a dedicated neuronal pathway comprising a GRP-GRPR cascade for itch. However, our studies, along with the others, do not support their claims.FindingsWe were unable to reproduce the immunostaining of BNP and NPRA as shown by Mishra and Hoon. By contrast, we were able to detect Grp mRNA in DRGs using in situ hybridization and real time RT-PCR. We show that the expression pattern of Grp mRNA is comparable to that of GRP protein in DRGs. Pharmacological and genetic blockade of GRP-GRPR signaling does not significantly affect intrathecal BNP-induced scratching behavior. We show that BNP inhibits inflammatory pain and morphine analgesia.ConclusionsAccumulating evidence demonstrates that GRP is a key neurotransmitter in pruriceptors for mediating histamine-independent itch. BNP-NPRA signaling is involved in both itch and pain and does not function upstream of the GRP-GRPR dedicated neuronal pathway. The site of BNP action in itch and pain and its relationship with GRP remain to be clarified.

Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity

“…The thermal sensitivity of C2 correlates with the presence of Trpv1 and Trpv2 in the Nppb gene network and the role of NBP in thermal hyperalgesia [19,45]. Both C4 and C5 are MHNs (IS).…”

Cross-Inhibition of NMBR and GRPR Signaling Maintains Normal Histaminergic Itch Transmission

“…However, the number of neurons expressing Grp mRNA and GRP protein was consistently found to be ϳ8% and upregulated in DRG neurons, spinal primary afferents, and cutaneous nerve fibers in chronic itch conditions using IHC, ISH, or quantitative real-time PCR (Lagerström et al, 2010;Kagami et al, 2013;Nattkemper et al, 2013;Zhao et al, 2013;Liu et al, 2014;Takanami et al, 2014). Importantly, GRP immunostaining was completely lost in Grp KO mice Zhao et al, 2013), demonstrating that the anti-GRP antibody does not recognize other proteins.…”

“…B-type natriuretic peptide (BNP) and its receptor natriuretic peptide receptor-A (NPRA) have been proposed to act upstream of GRP-GRPR signaling (Mishra and Hoon, 2013). However, other studies found that the BNP-NPRA pathway is important for nociceptive processing and is independent of the GRP-GRPR pathway (Zhang et al, 2010;Vilotti et al, 2013;Liu et al, 2014). GRPR (or BB2) is a member of the mammalian bombesin (Bn) receptor family, which comprises the following two other receptor subtypes: neuromedin B receptor [NMBR (or BB1)] and bombesin receptor subtype 3 (BRS-3).…”

“…The latter is a distantly related member with little binding affinity to NMB or GRP (Battey and Wada, 1991;Kroog et al, 1995;Gonzalez et al, 2008;Jensen et al, 2008). GRP is expressed in ϳ8% of DRG neurons and 12% of trigeminal ganglion neurons that coexpress TRPV1 in rodents and is upregulated in chronic itch conditions (Sun and Chen, 2007;Zhao et al, 2013;Liu et al, 2014;Takanami et al, 2014). Similar to GRP, intrathecal injection of NMB could also induce scratching behavior (O'Donohue et al, 1984;Bishop et al, 1986;Moody and Merali, 2004;Su and Ko, 2011).…”

Spinal Functions of B-Type Natriuretic Peptide, Gastrin-Releasing Peptide, and Their Cognate Receptors for Regulating Itch in Mice

“…Anatomic and pharmacological studies have demonstrated that GRP-GRPR system acts downstream of the BNP-NPRA signaling in the pruriceptive circuit as an itchselective regulation by BNP (Mishra and Hoon, 2013). However, a series of experiments conducted later indicated that BNP is neither itch-specific nor functions upstream of the GRP-GRPR signaling pathway (Liu et al, 2014). It is important to clarify the anatomic and pharmacological relationship between BNP-NPRA and GRP-GRPR systems in spinal regulation of itch.…”