Overexpression of artemin in the tongue increases expression of TRPV1 and TRPA1 in trigeminal afferents and causes oral sensitivity to capsaicin and mustard oil

Elitt, Christopher M.; Malin, Sacha A.; Koerber, H. Richard; Davis, Brian M.; Albers, Kathryn M.

doi:10.1016/j.brainres.2008.06.119

Cited by 55 publications

(54 citation statements)

References 43 publications

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“…The cells expressing increased artemin mRNA have not been precisely identified but is presumed that they were keratinocytes. Artemin overexpression in mice, where the artemin gene was inserted after the K14 keratin promoter, produced a similar pattern of phenotypic changes of TRP channel expression in primary afferents, as well as behavioral changes, as found in the present study [2,23]. The in situ hybridization signals showing artemin mRNA apparently increased in the epidermis 1d after CFA injection (Figure 1O, R) suggesting that keratinocytes express increased artemin mRNA.…”

Section: Discussionsupporting

confidence: 83%

Peripherally Increased Artemin is a Key Regulator of TRPA1/V1 Expression in Primary Afferent Neurons

et al. 2015

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BackgroundArtemin, a member of the glial cell line-derived neurotrophic factor family, is known to have a variety of neuronal functions, and has been the subject of attention because it has interesting effects, including bi-directional results in modulation in neuropathic and inflammatory pain. It has been shown that the overexpression of artemin is associated with an increase in the expression of TRP family channels in primary afferents and subsequent hyperalgesia, and an increase in neuronal activity. The purpose of this study was to examine the peripheral synthesis of artemin in inflammatory and neuropathic pain models, and to demonstrate the effects of long-term or repeated application of artemin in vivo on pain behaviors and on the expression of TRP family channels. Further, the regulatory mechanisms of artemin on TRPV1/A1 were examined using cultured DRG neurons.ResultsWe have demonstrated that artemin is locally elevated in skin over long periods of time, that artemin signals significantly increase in deep layers of the epidermis, and also that it is distributed over a broad area of the dermis. In contrast, NGF showed transient increases after peripheral inflammation. It was confirmed that the co-localization of TRPV1/A1 and GFRα3 was higher than that between TRPV1/A1 and TrkA. In the peripheral sciatic nerve trunk, the synthesis of artemin was found by RT-PCR and in situ hybridization to increase at a site distal to a nerve injury. We demonstrated that in vivo repeated artemin injections into the periphery changed the gene expression of TRPV1/A1 in DRG neurons without affecting GFRα3 expression. Repeated artemin injections also induced mechanical and heat hyperalgesia. Using primary cultured DRG neurons, we found that artemin application significantly increased TRPV1/A1 expression and Ca2+ influx. Artemin-induced p38 MAPK pathway regulated the TRPV1 channel expression, however TRPA1 upregulation by artemin is not mediated through p38 MAPK.ConclusionsThese data indicate the important roles of peripherally-derived artemin on the regulation of TRPV1/A1 in DRG neurons in pathological conditions such as inflammatory and neuropathic pain.

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Section: Discussionsupporting

confidence: 83%

Peripherally Increased Artemin is a Key Regulator of TRPA1/V1 Expression in Primary Afferent Neurons

et al. 2015

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“…These concentrations are based on previous demonstrations of intraepidermal fiber staining. 10, 11, 15 Specificity of the GFRα3 antibody was previously shown using a GFRα3 knockout mouse. 12 All slides were stained with bisbenzamide (1:40,000, Sigma, St. Louis, MO.)…”

Section: Methodsmentioning

confidence: 80%

“…35 Likewise, an increase in GFRα3 immunostained fibers was found in artemin over-expressing mice. 10, 11 However, in the AEW model of dry skin no sprouting of GFRα3-positive fibers was observed. Neurturin is another potentially interesting GDNF family ligand but its role in pruritus is currently unknown.…”

Section: Discussionmentioning

confidence: 92%

“…16 Although TRPA1 was initially shown to be expressed in peptidergic sensory neurons, 45 recent data have demonstrated robust modulation of TRPA1 function in Ret-positive neurons and TRPA1 expression in non-peptidergic IB4-positive fibers that innervate the epidermis. 3, 6, 10, 11, 30, 31 While the hyperinnervation of Ret-positive neurons is consistent with a potential role in dry skin itch, functional studies are necessary to determine whether changes in neural sensitization or receptor expression occur after AEW treatment.…”

Section: Discussionmentioning

confidence: 99%

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Enhanced Nonpeptidergic Intraepidermal Fiber Density and an Expanded Subset of Chloroquine-Responsive Trigeminal Neurons in a Mouse Model of Dry Skin Itch

Valtcheva

Samineni

Golden

et al. 2015

The Journal of Pain

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Chronic pruritic conditions are often associated with dry skin and loss of epidermal barrier integrity. In this study, repeated application of acetone and ether, followed by water (AEW) to the cheek skin of mice produced persistent scratching behavior with no increase in pain-related forelimb wiping, indicating the generation of itch without pain. Cheek skin immunohistochemistry showed a 64.5% increase in total epidermal innervation in AEW-treated mice compared to water-treated controls. This increase was independent of scratching, because mice prevented from scratching by Elizabethan collars showed similar hyperinnervation. To determine the effects of dry skin treatment on specific subsets of peripheral fibers, we examined Ret-positive, CGRP-positive, and GFRα3-positive intraepidermal fiber density. AEW treatment increased Ret-positive fibers, but not CGRP-positive or GFRα3-positive fibers, suggesting that a specific subset of non-peptidergic fibers could contribute to dry skin itch. To test whether trigeminal ganglion neurons innervating the cheek exhibited altered excitability after AEW treatment, primary cultures of retrogradely labeled neurons were examined using whole-cell patch clamp electrophysiology. AEW treatment produced no differences in measures of excitability compared to water-treated controls. In contrast, a significantly higher proportion of trigeminal ganglion neurons were responsive to the non-histaminergic pruritogen chloroquine after AEW treatment. We conclude that non-peptidergic, Ret-positive fibers and chloroquine-sensitive neurons may contribute to dry skin pruritus.

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“…Similarly, GFLs potentiate capsaicin responses in dissociated DRG neurons recorded by Ca 2+ imaging, showing sensitization of TRPV1 + cells (45). However, specific changes in TRPV1 channel activity have not been reported, and the preponderance of data suggests that artemin-induced heat hyperalgesia is caused by increased TRPV1 expression (27,28,46,47). Moreover, unlike the established TRPM8 dependence of arteminand NGF-evoked cold allodynia (8) or the necessity of TRPV1 for NGF-induced heat hyperalgesia (36), the molecule determinants of GFL-evoked alterations in nociception in vivo are unknown (48).…”

Section: Discussionmentioning

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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Overexpression of artemin in the tongue increases expression of TRPV1 and TRPA1 in trigeminal afferents and causes oral sensitivity to capsaicin and mustard oil

Cited by 55 publications

References 43 publications

Peripherally Increased Artemin is a Key Regulator of TRPA1/V1 Expression in Primary Afferent Neurons

Peripherally Increased Artemin is a Key Regulator of TRPA1/V1 Expression in Primary Afferent Neurons

Enhanced Nonpeptidergic Intraepidermal Fiber Density and an Expanded Subset of Chloroquine-Responsive Trigeminal Neurons in a Mouse Model of Dry Skin Itch

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

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