Artemin Immunotherapy Is Effective in Preventing and Reversing Cystitis-Induced Bladder Hyperalgesia via TRPA1 Regulation

DeBerry, Jennifer J.; Saloman, Jami L.; Dragoo, Brian K.; Albers, Kathryn M.; Davis, Brian M.

doi:10.1016/j.jpain.2015.03.014

Cited by 37 publications

(37 citation statements)

References 41 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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“…VMR is traditionally considered a surrogate measure of nociception because it is sensitive to analgesics and it is augmented by distention into noxious ranges and by sensitization of afferent nerves (e.g. by inflammation/irritation) . In our experiments, VMR was triggered by urethral distention to pressures up to 40 cmH 2 O.…”

Section: Discussionmentioning

confidence: 84%

“…Painful stimulation such as noxious distention or irritation/inflammation of visceral organs (e.g. bladder/colon) results in visceral hyperalgesia and is positively correlated with increased neuronal pERK expression in regions of the dorsal horn receiving visceral sensory input . To further investigate a potential role of peripheral urethral 5‐HT signalling in nociception, we applied 5‐HT intra‐urethrally (1 μ m ; 15 min) and evaluated pERK activation in neurones located in the L6 segment of the spinal cord, which receives urethral afferent input.…”

Section: Resultsmentioning

confidence: 99%

Serotonergic paraneurones in the female mouse urethral epithelium and their potential role in peripheral sensory information processing

et al. 2017

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Aim The mechanisms underlying detection and transmission of sensory signals arising from visceral organs, such as the urethra, are poorly understood. Recently, specialized ACh-expressing cells embedded in the urethral epithelium have been proposed as chemosensory sentinels for detection of bacterial infection. Here, we examined the morphology and potential role in sensory signalling of a different class of specialized cells that express serotonin (5-HT), termed paraneurones. Methods Urethrae, dorsal root ganglia neurones and spinal cords were isolated from adult female mice and used for immunohistochemistry and calcium imaging. Visceromotor reflexes (VMRs) were recorded in vivo. Results We identified two morphologically distinct groups of 5-HT+ cells with distinct regional locations: bipolar-like cells predominant in the mid-urethra and multipolar-like cells predominant in the proximal and distal urethra. Sensory nerve fibres positive for calcitonin gene-related peptide, substance P, and TRPV1 were found in close proximity to 5-HT+ paraneurones. In vitro 5-HT (1 µm) stimulation of urethral primary afferent neurones, mimicking 5-HT release from paraneurones, elicited changes in the intracellular calcium concentration ([Ca2+]i) mediated by 5-HT2 and 5-HT3 receptors. Approximately 50% of 5-HT responding cells also responded to capsaicin with changes in the [Ca2+]i. In vivo intra-urethral 5-HT application increased VMRs induced by urethral distention and activated pERK in lumbosacral spinal cord neurones. Conclusion These morphological and functional findings provide insights into a putative paraneurone-neural network within the urethra that utilizes 5-HT signalling, presumably from paraneurones, to modulate primary sensory pathways carrying nociceptive and non-nociceptive (mechano-sensitive) information to the central nervous system.

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“…Artn, a ligand in the same family as Gdnf, was also found to be up-regulated and linked with Gfra1 and Gfra3. This demonstrates a coordinated increased expression of neurotrophins in enteric glia that are likely to signal via pelvic and lumbosacral mechanisms to promote visceral pain (Zhu et al, 2001;Albers et al, 2006;Malin et al, 2006;Yu et al, 2012;DeBerry et al, 2015;Wang et al, 2016;Queme et al, 2020).…”

Section: Figure 5 An Interactome Between Normal and Inflamed Colonicmentioning

confidence: 99%

A pharmacological interactome platform for discovery of pain mechanisms and targets

Wangzhou

Paige

Neerukonda

et al. 2020

Preprint

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Smith for help with the colonic single neuron sequencing data, Dr. Brian Gulbransen and lab for help with the enteric glia TRAP data and Dr. Zhenyu Xuan for clarifying TCGA metadata formats. We thank all the authors of the papers from which we used their sequencing data for their exemplary transparency in sharing the details of their work with us. AbstractCells communicate with each other through ligand and receptor interactions. In the case of the peripheral nervous system, these ligand-receptor interactions shape sensory experience. In disease states, such as chronic pain, these ligand-receptor interactions can change the excitability of target neurons augmenting nociceptive input to the CNS. While the importance of these cell to neuron interactions are widely acknowledged, they have not been thoroughly characterized. We sought to address this by cataloging how peripheral cell types interact with sensory neurons in the dorsal root ganglion (DRG) using RNA sequencing datasets. Using single cell sequencing datasets from mouse we created a comprehensive interactome map for how mammalian sensory neurons interact with 42 peripheral cell types. We used this knowledge base to understand how specific cell types and sensory neurons interact in disease states. In mouse datasets, we created an interactome of colonic enteric glial cells in the naïve and inflamed state with sensory neurons that specifically innervate this tissue. In human datasets, we created interactomes of knee joint macrophages from rheumatoid arthritis patients and pancreatic cancer samples with human DRG. Collectively, these interactomes highlight ligandreceptor interactions in mouse models and human disease states that reflect the complexity of cell to neuron signaling in chronic pain states. These interactomes also highlight therapeutic targets, such as the epidermal growth factor receptor (EGFR), which was a common interaction point emerging from our studies.In this formula stands for distance, and stands for gene expression level across all cells in the first condition and second condition respectively, stands for standard deviation and stands for mean.

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Artemin Immunotherapy Is Effective in Preventing and Reversing Cystitis-Induced Bladder Hyperalgesia via TRPA1 Regulation

Cited by 37 publications

References 41 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

Serotonergic paraneurones in the female mouse urethral epithelium and their potential role in peripheral sensory information processing

A pharmacological interactome platform for discovery of pain mechanisms and targets

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