natriuretic-peptide--brain and Pruritus

Periostin, an extracellular matrix and matricellular protein, binds to several types of integrins that transduce its signals. Its function in allergic inflammation is the establishment of sustained chronic inflammation through an amplification of T helper type 2‒immune responses. In addition, recent studies have shown a significant role of periostin in itch sensation through direct integrin-mediated stimulation of nerve fibers and interaction with immune and nonimmune cells (e.g., macrophages, eosinophils, basophils, and keratinocytes). The objective of this review is to describe the role of periostin in itch induction in human and animal models and its expression in human pruritic conditions.

Topics: Animals; Cell Adhesion Molecules; Humans; Integrins; Natriuretic Peptide, Brain; Pruritus; Sensation; TRPA1 Cation Channel

Chronic itch poses major health care and economic burdens worldwide. In 2013, B-type natriuretic peptide (BNP) was identified as an itch-selective neuropeptide and shown to be both necessary and sufficient to produce itch behaviour in mice. Since then, mechanistic studies of itch have increased, not only at central levels of the spinal relay of itch signalling but also in the periphery and skin. In this review, we have critically analysed recent findings from complementary pharmacological and physiological approaches, combined with genetic strategies to examine the role of BNP in itch transduction and modulation of other pruritic proteins. Additionally, potential targets and possible strategies against BNP signalling are discussed for developing novel therapeutics in itch. Overall, we aim to provide insights into drug development by altering BNP signalling to modulate disease symptoms in chronic itch, including conditions for which no approved treatment exists.

Topics: Animals; Mice; Natriuretic Peptide, Brain; Pruritus; Signal Transduction; Skin

Topics: Animals; Brain; Emotions; Humans; Natriuretic Peptide, Brain; Neuroimmunomodulation; Perception; Pruritus; Receptors, G-Protein-Coupled; Sensation

An itch is a common sensation that makes us want to scratch. Most short-term itches are caused by histamine, a chemical that is released by immune cells following an infection or in response to an allergic reaction. Chronic itching, on the other hand, is not usually triggered by histamine, and is typically the result of neurological or skin disorders, such as atopic dermatitis. The sensation of itching is generated by signals that travel from the skin to nerve cells in the spinal cord. Studies in mice have shown that the neuropeptides responsible for delivering these signals differ depending on whether or not the itch involves histamine: GRPs (short for gastrin-releasing proteins) convey histamine-independent itches, while NMBs (short for neuromedin B) convey histamine-dependent itches. It has been proposed that another neuropeptide called BNP (short for B-type natriuretic peptide) is able to transmit both types of itch signals to the spinal cord. But it remains unclear how this signaling molecule is able to do this. To investigate, Meng, Liu, Liu, Liu et al. carried out a combination of behavioral, molecular and pharmacological experiments in mice and nerve cells cultured in a laboratory. The experiments showed that BNP alone cannot transmit the sensation of itching, but it can boost itching signals that are triggered by histamine. It is widely believed that BNP activates a receptor protein called NPRA. However, Meng et al. found that the BNP actually binds to another protein which alters the function of the receptor activated by NMBs. These findings suggest that BNP modulates rather than initiates histamine-dependent itching by enhancing the interaction between NMBs and their receptor. Understanding how itch signals travel from the skin to neurons in the spinal cord is crucial for designing new treatments for chronic itching. The work by Meng et al. suggests that treatments targeting NPRA, which was thought to be a key itch receptor, may not be effective against chronic itching, and that other drug targets need to be explored.

Topics: Animals; Ganglia, Spinal; HEK293 Cells; Histamine; Humans; Male; Mice; Mice, Inbred C57BL; Natriuretic Peptide, Brain; Neurokinin B; Pruritus; Receptors, Atrial Natriuretic Factor; Signal Transduction; Spinal Cord

Topics: Animals; Behavior, Animal; Cells, Cultured; Dermatitis, Atopic; Ganglia, Spinal; Interleukins; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Natriuretic Peptide, Brain; Oncostatin M Receptor beta Subunit; Pruritus; Receptors, Interleukin; Signal Transduction; TRPA1 Cation Channel; TRPV Cation Channels

Itch is a protective sensation producing a desire to scratch. Pathologic itch can be a chronic symptom of illnesses such as uremia, cholestatic liver disease, neuropathies and dermatitis, however current therapeutic options are limited. Many types of cell surface receptors, including those present on cells in the skin, on sensory neurons and on neurons in the spinal cord, have been implicated in itch signaling. The role of G protein signaling in the regulation of pruriception is poorly understood. We identify here 2 G protein signaling components whose mutation impairs itch sensation. R7bp (a.k.a. Rgs7bp) is a palmitoylated membrane anchoring protein expressed in neurons that facilitates Gαi/o -directed GTPase activating protein activity mediated by the Gβ5/R7-RGS complex. Knockout of R7bp diminishes scratching responses to multiple cutaneously applied and intrathecally-administered pruritogens in mice. Knock-in to mice of a GTPase activating protein-insensitive mutant of Gαo (Gnao1 G184S/+) produces a similar pruriceptive phenotype. The pruriceptive defect in R7bp knockout mice was rescued in double knockout mice also lacking Oprk1, encoding the G protein-coupled kappa-opioid receptor whose activation is known to inhibit itch sensation. In a model of atopic dermatitis (eczema), R7bp knockout mice showed diminished scratching behavior and enhanced sensitivity to kappa opioid agonists. Taken together, our results indicate that R7bp is a key regulator of itch sensation and suggest the potential targeting of R7bp-dependent GTPase activating protein activity as a novel therapeutic strategy for pathological itch.

Topics: Animals; Camphor; Cells, Cultured; Chromones; Endothelin-1; Female; Ganglia, Spinal; Gastrin-Releasing Peptide; Gene Expression Regulation; GTP-Binding Protein alpha Subunits, Gi-Go; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Natriuretic Peptide, Brain; Nociception; Pain Threshold; Pruritus; Psychomotor Performance; Receptors, Opioid, kappa; RGS Proteins; Sensation; Sensory Receptor Cells

B-type natriuretic peptide (BNP)-natriuretic peptide receptor A (NPRA) and gastrin-releasing peptide (GRP)-GRP receptor (GRPR) systems contribute to spinal processing of itch. However, pharmacological and anatomic evidence of these two spinal ligand-receptor systems are still not clear. The aim of this study was to determine the spinal functions of BNP-NPRA and GRP-GRPR systems for regulating scratching activities in mice by using pharmacological and immunohistochemical approaches. Our results showed that intrathecal administration of BNP (0.3-3 nmol) dose dependently elicited scratching responses, which could be blocked by the NPRA antagonist (Arg6,β-cyclohexyl-Ala8,D-Tic16,Arg17,Cys18)-atrial natriuretic factor(6-18) amide (A71915). However, A71915 had no effect on intrathecal GRP-induced scratching. In contrast, pretreatment with a GRPR antagonist (D-Tpi6,Leu13ψ(CH2-NH)-Leu14)bombesin(6-14) (RC-3095) inhibited BNP-induced scratching. Immunostaining revealed that NPRA proteins colocalize with GRP, but not GRPR, in the superficial area of dorsal horn, whereas BNP proteins do not colocalize with either GRP or GRPR in the dorsal horn. Intradermal administration of ligands including endothelin-1, U-46619, bovine adrenal medulla 8-22, and Ser-Leu-Ile-Gly-Arg-Leu-NH2 (SLIGRL) increased scratching bouts at different levels of magnitude. Pretreatment with intrathecal A71915 did not affect scratching responses elicited by all four pruritogens, whereas pretreatment with RC-3095 only inhibited SLIGRL-induced scratching. Interestingly, immunostaining showed that RC-3095, but not A71915, inhibited SLIGRL-elicited c-Fos activation in the spinal dorsal horn, which was in line with behavioral outcomes. These findings demonstrate that: 1) BNP-NPRA system may function upstream of the GRP-GRPR system to regulate itch in the mouse spinal cord, and 2) both NPRA and GRPR antagonists may have antipruritic efficacy against centrally, but not peripherally, elicited itch.

Topics: Animals; Atrial Natriuretic Factor; Bombesin; Gastrin-Releasing Peptide; Male; Mice; Natriuretic Peptide, Brain; Peptide Fragments; Pruritus; Receptors, Atrial Natriuretic Factor; Receptors, Bombesin; Spinal Cord; Tetrahydroisoquinolines

Spinal itch transmission has been reported to be mediated by at least two neuronal populations in spinal dorsal horn, neurons expressing brain-natriuretic peptide (BNP) receptor (Npra) and gastrin-releasing peptide (GRP) receptor (GRPR). Although Npra-expressing neurons were shown to be upstream of GRPR- expressing neurons in spinal itch transmission, the roles of BNP and GRP in the spinal neurotransmission of histamine-dependent and -independent itch remains unclear. Using in vivo electrophysiology and behavior analysis, this study examined the responses of chloroquine (histamine-independent pruritogen)-responsive and histamine-responsive dorsal horn neurons to spinal applications of BNP and GRP. Electrophysiologically, 9.5% of chloroquine-responsive neurons responded to BNP, 33.3% to GRP, and 4.8% to both, indicating that almost half of chloroquine-responsive neurons were unresponsive to both BNP and GRP. In contrast, histamine-responsive neurons did not respond to spinal BNP application, whereas 30% responded to spinal GRP application, indicating that 70% of histamine-responsive neurons were unresponsive to both BNP and GRP. Behavioral analyses showed differences in the time-course and frequency of scratching responses evoked by intrathecal BNP and GRP. These findings provide evidence that most BNP-Npra and GRP-GRPR signaling involve different pathways of spinal itch transmission, and that multiple neurotransmitters, in addition to BNP and GRP, are involved in spinal itch transmission. The electrophysiological results also suggest that spinal BNP contributes little to histaminergic itch directly.

Topics: Action Potentials; Animals; Chloroquine; Gastrin-Releasing Peptide; Histamine; Male; Mice; Mice, Inbred C57BL; Natriuretic Peptide, Brain; Posterior Horn Cells; Pruritus

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.

Topics: Animals; Ganglia, Spinal; Gastrin-Releasing Peptide; Gene Expression Regulation; Inflammation; Male; Mice; Mice, Inbred C57BL; Natriuretic Peptide, Brain; Pain; Pruritus; Receptors, Atrial Natriuretic Factor; Receptors, Bombesin; RNA, Messenger; Signal Transduction; Spinal Cord

Itch is triggered by somatosensory neurons expressing the ion channel TRPV1 (transient receptor potential cation channel subfamily V member 1), but the mechanisms underlying this nociceptive response remain poorly understood. Here, we show that the neuropeptide natriuretic polypeptide b (Nppb) is expressed in a subset of TRPV1 neurons and found that Nppb(-/-) mice selectively lose almost all behavioral responses to itch-inducing agents. Nppb triggered potent scratching when injected intrathecally in wild-type and Nppb(-/-) mice, showing that this neuropeptide evokes itch when released from somatosensory neurons. Itch responses were blocked by toxin-mediated ablation of Nppb-receptor-expressing cells, but a second neuropeptide, gastrin-releasing peptide, still induced strong responses in the toxin-treated animals. Thus, our results define the primary pruriceptive neurons, characterize Nppb as an itch-selective neuropeptide, and reveal the next two stages of this dedicated neuronal pathway.

Topics: Animals; Chloroquine; Endothelin-1; Gastrin-Releasing Peptide; Histamine; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Natriuretic Peptide, Brain; Nociception; Phospholipase C beta; Pruritus; Receptors, Atrial Natriuretic Factor; Sensory Receptor Cells; Spinal Cord; TRPV Cation Channels

Topics: Animals; Male; Natriuretic Peptide, Brain; Nociception; Pruritus; Sensory Receptor Cells; Transient Receptor Potential Channels