Artemin causes hypersensitivity to warm sensation, mimicking warmth-provoked pruritus in atopic dermatitis

Murota, Hiroyuki; Izumi, Mayuko; El-latif, Mostafa I. Abd; Nishioka, Motomu; Terao, Mineko; Tani, Mizuki; Matsui, Saki; Sano, Shigetoshi; Katayama, Ichiro

doi:10.1016/j.jaci.2012.05.027

Cited by 88 publications

(67 citation statements)

References 37 publications

(39 reference statements)

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“…In mice, intradermal artemin injections cause abnormal sensory nerve sprouting and thermal hyperalgesia. In transgenic mice, skinexpressed artemin is retrogradely transported into the sensory ganglia, where it increases TRPV1 expression (Murota et al, 2012). These findings give further credence to the PAC-14028 trials.…”

Section: Dietary Mgmentioning

confidence: 60%

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

2014

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Section: Dietary Mgmentioning

confidence: 60%

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

2014

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“…The molecular processes whereby NGF/TrkA activation leads to heat hyperalgesia are well-documented (7), but to date, the molecular nature of GFL signaling on nociception has yet to be elucidated. For example, we and others have shown that acute exposure of GFLs, including artemin, in vivo leads to heat hyperalgesia (8,42,45). Similarly, GFLs potentiate capsaicin responses in dissociated DRG neurons recorded by Ca 2+ imaging, showing sensitization of TRPV1 + cells (45).…”

Section: Discussionmentioning

confidence: 74%

“…However, in addition to direct sensitization of nociceptors, NGF also acts indirectly through activation of various peripheral cell types and the subsequent release of a host of inflammatory mediators, which in turn, sensitize sensory afferents (12,(39)(40)(41). Several inflammatory conditions stimulate artemin release from a number of peripheral cell types, including keratinocytes, fibroblasts, and immune cells (28,42,43), and we hypothesized that NGF-induced cold allodynia was mediated by NGF indirectly promoting artemin release. To test this hypothesis, we again used artemin-neutralizing antibodies and found that NGF-evoked cold allodynia observed in control mice (Fig.…”

Section: Significancementioning

confidence: 99%

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

Lippoldt

Ongun

Kusaka

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tissue injury prompts the release of a number of proalgesic molecules that induce acute and chronic pain by sensitizing pain-sensing neurons (nociceptors) to heat and mechanical stimuli. In contrast, many proalgesics have no effect on cold sensitivity or can inhibit cold-sensitive neurons and diminish cooling-mediated pain relief (analgesia). Nonetheless, cold pain (allodynia) is prevalent in many inflammatory and neuropathic pain settings, with little known of the mechanisms promoting pain vs. those dampening analgesia. Here, we show that cold allodynia induced by inflammation, nerve injury, and chemotherapeutics is abolished in mice lacking the neurotrophic factor receptor glial cell line-derived neurotrophic factor family of receptors-α3 (GFRα3). Furthermore, established cold allodynia is blocked in animals treated with neutralizing antibodies against the GFRα3 ligand, artemin. In contrast, heat and mechanical pain are unchanged, and results show that, in striking contrast to the redundant mechanisms sensitizing other modalities after an insult, cold allodynia is mediated exclusively by a single molecular pathway, suggesting that artemin-GFRα3 signaling can be targeted to selectively treat cold pain.W hen pain continues past its usefulness as a warning of potential tissue damage, it becomes a debilitating condition for which few viable treatments are currently available. The result can be an exacerbation of pain in response to both innocuous (allodynia) and noxious (hyperalgesia) stimuli (1). For example, pain felt with normally pleasant mild cooling (cold allodynia) occurs in many pathological conditions, such as fibromyalgia, multiple sclerosis, stroke, and chemotherapeutic-induced polyneuropathy, but what underlies this specific form of pain at the cellular or molecular level is largely unknown (2-5). Pain-sensing afferent neurons (nociceptors) are sensitized during injury or disease, in part, by a vast array of proalgesic compounds termed the "inflammatory soup" (e.g., neurotrophic factors, protons, bradykinin, prostaglandins, and ATP) (1). These substances are released locally at the site of injury by infiltrating immune cells, such as macrophages, neutrophils, and T cells, as well as resident cells, including keratinocytes and mast cells (6), and either directly activate sensory receptors or sensitize them to subsequent stimuli (7). Moreover, prolonged inflammation can lead to central sensitization (in the spinal cord and brain) and bring about long-lasting chronic pain that persists after acute inflammation has resolved. Thus, a better understanding of the molecules involved in neuroinflammation may lead to therapeutic options for acute and chronic pain.Of the range of proalgesics known to promote pain, only nerve growth factor (NGF) and the glial cell line-derived neurotrophic factor family ligand (GFL) artemin have been shown to lead to cold hypersensitivity (8-11). Both are major components of the inflammatory soup and produce nociceptor sensitization and pain through their cognate cell surface rece...

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“…Artemin-expressing fibroblasts have been shown to accumulate in skin lesions of patients with atopic dermatitis. 28) Moreover, dermal fibroblasts secrete artemin in response to substance P, released by cutaneous nerve fibers, inducing itch and/or neurogenic inflammation via the activation of neurokinin-1 (nk-1) receptor. 29) Intradermal injection of artemin into mice resulted in peripheral nerve sprouting and thermal hyperalgesia.…”

Section: Nerve Elongation Factorsmentioning

confidence: 99%

“…29) Intradermal injection of artemin into mice resulted in peripheral nerve sprouting and thermal hyperalgesia. 28) therefore, artemin may be partly involved in hypersensitivity to warm sensations, mimicking warmthprovoked itch in atopic dermatitis.…”

Section: Nerve Elongation Factorsmentioning

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

show abstract

Artemin causes hypersensitivity to warm sensation, mimicking warmth-provoked pruritus in atopic dermatitis

Cited by 88 publications

References 37 publications

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

An Update on Peripheral Mechanisms and Treatments of Itch

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