The Neuropeptide Y Y₂ Receptor Is Coexpressed with Nppb in Primary Afferent Neurons and Y₂ Activation Reduces Histaminergic and IL-31-Induced Itch

Abstract

Itch stimuli are detected by specialized primary afferents that convey the signal to the spinal cord, but how itch transmission is regulated is still not completely known. Here, we investigated the roles of the neuropeptide Y (NPY)/Y 2 receptor system on scratch behavior. The inhibitory Y 2 receptor is expressed on mouse primary afferents, and intrathecal administration of the Y 2 agonist peptide YY (PYY) 3-36 reduced scratch episode frequency and duration induced by compound 48/80, an effect that could be reversed by intrathecal preadministration of the Y 2 antagonist BIIE0246. Also, scratch episode duration induced by histamine could be reduced by PYY 3-36. In contrast, scratch behavior induced by a-methyl-5HT, protease-activated receptor-2-activating peptide SLIGRL, chloroquine, topical dust mite extract, or mechanical itch induced by von Frey filaments was unaffected by stimulation of Y 2. Primary afferent neurons expressing the Npy2r gene were found to coexpress itch-associated markers such as natriuretic peptide precursor b, oncostatin M receptor, and interleukin (IL) 31 receptor A. Accordingly, intrathecal PYY 3-36 reduced the scratch behavior induced by IL-31. Our findings imply that the NPY/Y 2 system reduces histaminergic and IL-31-associated itch through presynaptic inhibition of a subpopulation of itch-associated primary afferents. SIGNIFICANCE STATEMENT The spinal neuropeptide Y system dampens scratching behavior induced by histaminergic compounds and interleukin 31, a cytokine involved in atopic dermatitis, through interactions with the Y 2 receptor. The Y 2 receptor is expressed by primary afferent neurons that are rich in itch-associated neurotransmitters and receptors such as somatostatin, natriuretic peptide precursor b, and interleukin 31 receptors.

Single Cell Transcriptomic Analysis of Spinal Dmrt3 Neurons in Zebrafish and Mouse Identifies Distinct Subtypes and Reveal Novel Subpopulations Within the dI6 Domain

“…Genes encoding endogenous opioid ligands were expressed in mouse; Penk , which gives rise to enkephalin and BAM8–22 (bovine adrenal medulla 8–22 peptide) was expressed in the M1 cluster and Pnoc , which forms Nociceptin/orphanin FQ (N/OFQ), was expressed in multiple clusters ( Figure 5D ; Houtani et al, 1996 ; Abbadie and Pasternak, 2006 ). There was also strong expression of Npy in M4 and M5, which has been associated with both pain and itch sensation ( Gao et al, 2018 ; Jakobsson et al, 2019 ; Ma et al, 2020 ; Nelson and Taylor, 2021 ).…”

Molecular and cellular mechanisms of itch and pain in atopic dermatitis and implications for novel therapeutics

“…Neuropeptide Y reduces IL‐31–mediated itch via presynaptic inhibition of afferent neurons. 80 Substance P and NGF promote itch. Stimulated nerve fibres, which secrete substance P, vasoactive intestinal peptide and somatostatin, activate mast cells, which regulate nerve function.…”

“…Several GPCRs also mediate itch and pain, including Mrgpr family members and PAR‐2, as mentioned previously. 68 , 72 Neuropeptide Y, 80 mu opioids, 84 prostaglandin D 2 85 and substance P signal through GPCRs. 86 The G protein–coupled oestrogen receptor modulates the effects of a TNF‐α–induced protein called A20 that is increased by formononetin, which attenuates AD.…”

Current views on neuropeptides in atopic dermatitis

“…36,37,50 Recently, more and more studies have proved that NPY plays a role in gating itching signal pathways in the spinal cord, mainly inhibiting mechanical itch, but it may also have the inhibitory function on histamine itch and IL-31 itch. [51][52][53] Y1R and Y2R were found in primary afferent neurons and itching neurons expressing gastrinreleasing peptide (GRP), suggesting that NPY may regulate itch sensation by inhibiting the itching signalling molecules released in the spinal cord. Intrathecal administration of Y2 receptor agonist YY (PYY) 3-36 can suppress itching caused by IL-31.…”

“…Intrathecal administration of Y2 receptor agonist YY (PYY) 3-36 can suppress itching caused by IL-31. 54 Neuropeptide Y mainly promotes the infiltration of inflammatory cells and regulates the formation of itching. Since inflammatory cell infiltration and itching are the main features of AD, NPY is expected to become a therapeutic target in AD treatment.…”