Center for the Study of Itch, Washington University School of Medicine Pain Center, St, Louis, MO 63110, USA.
Mol Pain. 2014 Jan 18;10:4. doi: 10.1186/1744-8069-10-4.
A 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.
We 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.
Accumulating 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.
Mishra 和 Hoon 的一项最新研究确定 B 型利钠肽（BNP）是一种重要的瘙痒传递肽，并提出 BNP 激活脊髓利钠肽受体-A（NPRA）表达神经元，这些神经元释放胃泌素释放肽（GRP）激活 GRP 受体（GRPR）表达神经元，从而将瘙痒信息从外周传递到大脑（Science 340：968-971，2013）。这一新途径有效性的一个核心前提是背根神经节（DRG）神经元中不存在 GRP。为此，他们表明 DRG 神经元中的 Grp mRNA 要么不存在，要么几乎检测不到，并声称 BNP 而不是 GRP 是瘙痒感受器中的主要神经递质。他们表明，NPRA 免疫染色与脊髓中的 Grp-eGFP 完美共定位，并且测试了 Nppb-/- 小鼠的一些急性疼痛行为。他们声称 BNP 是一种瘙痒选择性肽，作为包含 GRP-GRPR 级联反应的专门神经元途径的第一站，用于瘙痒。然而，我们的研究以及其他研究并不支持他们的观点。
我们无法复制 Mishra 和 Hoon 所示的 BNP 和 NPRA 的免疫染色。相比之下，我们能够使用原位杂交和实时 RT-PCR 在 DRG 中检测到 Grp mRNA。我们表明 Grp mRNA 的表达模式与 DRG 中 GRP 蛋白的表达模式相当。GRP-GRPR 信号的药理学和遗传阻断对鞘内 BNP 诱导的搔抓行为没有显著影响。我们表明 BNP 抑制炎症性疼痛和吗啡镇痛。
越来越多的证据表明，GRP 是介导组胺非依赖性瘙痒的痒感受器中的关键神经递质。BNP-NPRA 信号转导参与瘙痒和疼痛，并且不在 GRP-GRPR 专用神经元途径的上游起作用。BNP 在瘙痒和疼痛中的作用部位及其与 GRP 的关系仍有待阐明。
