Artemin–GFRα3 interactions partially contribute to acute inflammatory hypersensitivity

Thornton, Peter; Hatcher, Jon P.; Robinson, Ian; Sargent, Becky; Franzén, Bo; Martino, Giovanni; Kitching, Lisa; Glover, Colin P.; Anderson, Dina; Forsmo-Bruce, Heidi; Low, Choon Pei; Cusdin, Fiona; Dosanjh, Bhupinder; Williams, Wendy A.; Steffen, Anȷa; Thompson, Simon; Eklund, Malin; Lloyd, Chris J.; Chessell, Iain P.; Hughes, Jane P.

doi:10.1016/j.neulet.2013.04.007

Cited by 28 publications

(24 citation statements)

References 19 publications

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“…Artemin-neutralizing antibodies can ameliorate both inflammatory and neuropathic cold pain, which has already been established in the animal, suggesting that interfering with artemin is a potential therapeutic strategy for this pain modality. Our results are consistent with other recent reports that suggest that artemin neutralization was found to inhibit noninflammatory heat hyperalgesia in the tongue and reduce bladder hyperalgesia (33)(34)(35). Moreover, this approach is analogous to therapeutic interventions to block pain with NGF-neutralizing antibodies that are currently ongoing (64,65).…”

Section: Discussionsupporting

confidence: 92%

“…Because of this extraordinary specificity, we hypothesized that in vivo artemin neutralization in mouse models of inflammatory and neuropathic pain could selectively block cold allodynia, even that which is localized at or near a site of injury, whereas heat and mechanical pain would remain intact. Arteminneutralizing antibodies are known to effectively inhibit binding of artemin with GFRα3 in vivo and serve as a potential pharmacological mechanism to ameliorate or prevent the effects of artemin exposure (33)(34)(35). Therefore, we tested whether a systemic injection of an established artemin-neutralizing mAb could reverse inflammatory and neuropathic pain.…”

Section: Significancementioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 92%

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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“…Injection of Artn causes thermal hypersensitivity that lasts over 24 h [6,7]. To determine if activation of nAChRs contributes to this transient sensitivity we examined the effect of nAChR antagonists on Artn-induced behavioral hyperalgesia.…”

Section: Resultsmentioning

confidence: 99%

“…In rodents, experimentally induced inflammation of the skin increases the level of Artn mRNA and this increase parallels the time course of thermal hyperalgesia [6,7]. Other studies have shown that injection of anti-Artn antibodies provides a partial reversal of complete Freund’s adjuvant (CFA)-induced mechanical hypersensitivity [7]. In addition, cultured DRG neurons grown in the presence of Artn exhibit enhanced capsaicin-evoked Ca 2+ influx and release of CGRP [8].…”

Section: Introductionmentioning

confidence: 99%

Artemin Growth Factor Increases Nicotinic Cholinergic Receptor Subunit Expression and Activity in Nociceptive Sensory Neurons

et al. 2014

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BackgroundArtemin (Artn), a member of the glial cell line-derived growth factor (GDNF) family, supports the development and function of a subpopulation of peptidergic, TRPV1-positive sensory neurons. Artn (enovin, neublastin) is elevated in inflamed tissue and its injection in skin causes transient thermal hyperalgesia. A genome wide expression analysis of trigeminal ganglia of mice that overexpress Artn in the skin (ART-OE mice) showed elevation in nicotinic acetylcholine receptor (nAChR) subunits, suggesting these ion channels contribute to Artn-induced sensitivity. Here we have used gene expression, immunolabeling, patch clamp electrophysiology and behavioral testing assays to investigate the link between Artn, nicotinic subunit expression and thermal hypersensitivity.ResultsReverse transcriptase-PCR validation showed increased levels of mRNAs encoding the nAChR subunits α3 (13.3-fold), β3 (4-fold) and β4 (7.7-fold) in trigeminal ganglia and α3 (4-fold) and β4 (2.8-fold) in dorsal root ganglia (DRG) of ART-OE mice. Sensory ganglia of ART-OE mice had increased immunoreactivity for nAChRα3 and exhibited increased overlap in labeling with GFRα3-positive neurons. Patch clamp analysis of back-labeled cutaneous afferents showed that while the majority of nicotine-evoked currents in DRG neurons had biophysical and pharmacological properties of α7-subunit containing nAChRs, the Artn-induced increase in α3 and β4 subunits resulted in functional channels. Behavioral analysis of ART-OE and wildtype mice showed that Artn-induced thermal hyperalgesia can be blocked by mecamylamine or hexamethonium. Complete Freund’s adjuvant (CFA) inflammation of paw skin, which causes an increase in Artn in the skin, also increased the level of nAChR mRNAs in DRG. Finally, the increase in nAChRs transcription was not dependent on the Artn-induced increase in TRPV1 or TRPA1 in ART-OE mice since nAChRs were elevated in ganglia of TRPV1/TRPA1 double knockout mice.ConclusionsThese findings suggest that Artn regulates the expression and composition of nAChRs in GFRα3 nociceptors and that these changes contribute to the thermal hypersensitivity that develops in response to Artn injection and perhaps to inflammation.

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“…An interesting observation is that GFRa3 receptors largely co-localise (99%) with TRPV1 channels (Orozco et al, 2001). The in vivo activity of artemin has been mainly associated with nociceptive actions (Elitt et al, 2006;Malin et al, 2006;Ceyhan et al, 2010;Murota et al, 2012;Lippoldt et al, 2013;Thornton et al, 2013). Akin to other neurotrophins, artemin induces thermal hyperalgesia in vivo and in vitro by sensitizing thermoTRP receptors (Elitt et al, 2006(Elitt et al, , 2008Malin et al, 2006;Lippoldt et al, 2013), most likely through Ret-dependent and -independent mechanisms.…”

Section: Neurotrophin Signallingmentioning

confidence: 99%

Neurotrophins, endocannabinoids and thermo‐transient receptor potential: a threesome in pain signalling

Devesa

Ferrer-Montiel

2014

Eur J of Neuroscience

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Because of the social and economic costs of chronic pain, there is a growing interest in unveiling the cellular and molecular mechanisms underlying it with the aim of developing more effective medications. Pain signalling is a multicomponent process that involves the peripheral and central nervous systems. At the periphery, nociceptor sensitisation by pro-inflammatory mediators is a primary step in pain transduction. Although pain is multifactorial at cellular and molecular levels, it is widely accepted that neurotrophin (TrkA, p75NTR, Ret and GFRs), cannabinoid (CB1 and CB2), and thermo-transient receptor potential (TRPs; TRPV1, TRPA1 and TRPM8) receptors play a pivotal role. They form a threesome for which endocannabinoids appear to be a first line of defence against pain, while neurotrophins and thermoTRPs are the major generators of painful signals. However, endocannabinoids may exhibit nociceptive activity while some neurotrophins may display anti-nociception. Accordingly, a clear-cut knowledge of the modulation and context-dependent function of these signalling cascades, along with the molecular and dynamic details of their crosstalk, is critical for understanding and controlling pain transduction. Here, the recent progress in this fascinating topic, as well as the tantalizing questions that remain unanswered, will be discussed. Furthermore, we will underline the need for using a systems biology approach (referred to as systems pain) to uncover the dynamics and interplay of these intricate signalling cascades, taking into consideration the molecular complexity and cellular heterogeneity of nociceptor populations. Nonetheless, the available information confirms that pharmacological modulation of this signalling triad is a highly valuable therapeutic strategy for effectively treating pain syndromes.

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Artemin–GFRα3 interactions partially contribute to acute inflammatory hypersensitivity

Cited by 28 publications

References 19 publications

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

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

Artemin Growth Factor Increases Nicotinic Cholinergic Receptor Subunit Expression and Activity in Nociceptive Sensory Neurons

Neurotrophins, endocannabinoids and thermo‐transient receptor potential: a threesome in pain signalling

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