Serum Gastrin-Releasing Peptide Levels Correlate with Pruritus in Patients with Atopic Dermatitis

Kagami, Shinji; Sugaya, Makoto; Suga, Hiraku; Morimura, Sohshi; Kai, Hiromichi; Ohmatsu, Hanako; Fujita, Hideki; Tsunemi, Yuichiro; Sato, Shinichi

doi:10.1038/jid.2013.38

Cited by 31 publications

(25 citation statements)

References 13 publications

(14 reference statements)

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“…Identification of ERK-dependent transcriptional events would be a logical next step to link extracellular stimuli to the expression of downstream effector genes that encode itch information. Finally, the present study supports the role of GRP as an itch-specific neuropeptide in sensory neurons, in agreement with previous findings that GRP was upregulated in primary afferents of primates with chronic itch (53) and in patients (54).…”

Section: Figuresupporting

confidence: 93%

Chronic itch development in sensory neurons requires BRAF signaling pathways

Zhao¹,

Huo²,

Jeffry³

et al. 2013

J. Clin. Invest.

104

154

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Chronic itch, or pruritus, is associated with a wide range of skin abnormalities. The mechanisms responsible for chronic itch induction and persistence remain unclear. We developed a mouse model in which a constitutively active form of the serine/threonine kinase BRAF was expressed in neurons gated by the sodium channel Nav1.8 (BRAF Nav1.8 mice). We found that constitutive BRAF pathway activation in BRAF Nav1.8 mice results in ectopic and enhanced expression of a cohort of itch-sensing genes, including gastrin-releasing peptide (GRP) and MAS-related GPCR member A3 (MRGPRA3), in nociceptors expressing transient receptor potential vanilloid 1 (TRPV1). BRAF Nav1.8 mice showed de novo neuronal responsiveness to pruritogens, enhanced pruriceptor excitability, and heightened evoked and spontaneous scratching behavior. GRP receptor expression was increased in the spinal cord, indicating augmented coding capacity for itch subsequent to amplified pruriceptive inputs. Enhanced GRP expression and sustained ERK phosphorylation were observed in sensory neurons of mice with allergic contact dermatitis-or dry skin-elicited itch; however, spinal ERK activation was not required for maintaining central sensitization of itch. Inhibition of either BRAF or GRP signaling attenuated itch sensation in chronic itch mouse models. These data uncover RAF/MEK/ERK signaling as a key regulator that confers a subset of nociceptors with pruriceptive properties to initiate and maintain long-lasting itch sensation. IntroductionThe ability of the brain to discriminate pain from itch in order to make binary decisions -eliciting either withdrawal or scratching behavior -is critically dependent on the functional connectivity of the somatosensory system. Itch information, along with pain, is conveyed by primary afferents of the dorsal root ganglion (DRG) to the spinal cord and of the trigeminal ganglion neurons to the trigeminal subnucleus caudalis of the brainstem, respectively, which in turn supplies input to the somatosensory cortex through spinothalamic tract or trigeminothalamic tract neurons (1-4). At the molecular level, emerging evidence suggests that activation of GPCRs in sensory neurons is likely responsible for relaying distinct types of acute stimulus-evoked itch (5-7). In addition, several transient receptor potential (TRP) channels, including TRP vanilloid 1 (TRPV1) and TRPA1, have been implicated in mediating histaminergic and nonhistaminergic itch, respectively (8-10). In the spinal cord, gastrin-releasing peptide (GRP) receptor (GRPR) and neurons expressing GRPR are key mediators dedicated to the coding of itch sensation (11-13). In contrast to acute itch, chronic itch may arise from an altered or diseased state of the

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Section: Figuresupporting

confidence: 93%

Chronic itch development in sensory neurons requires BRAF signaling pathways

Zhao¹,

Huo²,

Jeffry³

et al. 2013

J. Clin. Invest.

104

154

View full text Add to dashboard Cite

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“…GRP-positive nerve fibers are increased in the skin of patients with atopic dermatitis and mice with chronic allergic dermatitis, 76,77) and GRP released from primary afferents may degranulate mast cells. 78) GRP and BB 2 receptor seem to be interesting targets for pruritus, although their roles in pathological pruritus remain unclear.…”

Section: )mentioning

confidence: 97%

Potential New Therapeutic Targets for Pathological Pruritus

Kuraishi

2013

Biological & Pharmaceutical Bulletin

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Very few approved medications are indicated for the treatment of pruritus, and drug development for pruritic diseases is awaited. During the past two decades, progress has been made in understanding the molecular basis of the physiology and pathophysiology of pruritus. Newly identified potential targets for pathological pruritus include receptors (histamine H 4 receptor, leukotriene B 4 receptors, interleukin-31 receptor A, bombesin BB 2 receptor, toll-like receptor 3, α-adrenoceptor, and opioid μ-and κ-receptors), channels (transient receptor potential (TRP) V3 and TRPA1 channels), and enzymes (histidine decarboxylase, sphingomyelin glucosylceramide deacylase, 5-lipoxygenase, leukotriene A 4 hydrolase, and autotaxin). The development of specific, effective blockers and agonists/antagonists of these targets is awaited.

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“…45) A more recent study showed that serum GRP levels correlate with pruritus in patients with atopic dermatitis. 46) thus, serum GrP level may be useful as a biomarker for itch and disease severity in patients with atopic dermatitis.…”

Section: Gastrin-releasing Peptide (Grp)mentioning

confidence: 99%

An Update on Peripheral Mechanisms and Treatments of Itch

Tominaga

Takamori

2013

Biological & Pharmaceutical Bulletin

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Histamine H 1 -receptor blockers are used to treat all types of itch resulting from serious skin diseases such as atopic dermatitis, as well as from renal and liver diseases. However, they often lack efficacy in chronic itch, a profound clinical problem that decreases quality of life. The development of effective treatments requires a full understanding of the fundamental mechanisms of itch. Recent studies have indicated that the pathogenic mechanisms of itch also involve agonists other than histamine, including proteases, neuropeptides, cytokines, and opioids, as well as their cognate receptors. Release of these pruritogenic mediators and modulators into the periphery may directly activate itch-mediating C-fibers via specific receptors on the nerve terminals. Histological observations have shown increased epidermal nerve densities in patients with atopic dermatitis, suggesting that the higher density is at least partly responsible for itch sensitization. This

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Serum Gastrin-Releasing Peptide Levels Correlate with Pruritus in Patients with Atopic Dermatitis

Cited by 31 publications

References 13 publications

Chronic itch development in sensory neurons requires BRAF signaling pathways

Chronic itch development in sensory neurons requires BRAF signaling pathways

Potential New Therapeutic Targets for Pathological Pruritus

An Update on Peripheral Mechanisms and Treatments of Itch

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