An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways

Deuis, Jennifer R.; Zimmermann, Katharina; Romanovsky, Andrej A.; Possani, Lourival D.; Cabot, Peter J.; Lewis, Richard J.; Vetter, Irina

doi:10.1016/j.pain.2013.05.032

Cited by 151 publications

(212 citation statements)

References 58 publications

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“…For example, two-pore, nongated potassium channels contribute to cold pain as they are down-regulated after oxaliplatin treatment, thereby leading to enhanced neuronal excitability (61,62). Moreover, antagonism of the voltage-gated sodium channel Nav1.6 attenuated neuropathic cold allodynia (63). Thus, the mechanisms that potentiate cold responses at the molecular and cellular levels are diverse, but our data strongly suggest that future studies into cold pain should center around the effect of GFRα3 activation on these pathways.…”

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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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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“…Two other isoforms distributed throughout the nervous system, Na V 1.6 and Na V 1.8, have also been subjects of intense research concerning their role in the conduction of pain signals 2,[132][133][134][135] . Na V 1.9 had also shown an involvement in pain 136,137 , however a lack of Na V 1.9 assays and Na V 1.9 selective modulators have greatly hampered the isoform's therapeutic potential.…”

Section: Potassium Channelsmentioning

confidence: 99%

“…Cells were split every 3-6 days in a ratio of 1:5 using 0.25% trypsin/EDTA. Cells were plated on T75 cm 2 Each assay with Na V 1.6-expressing HEK293 cells or Na V 1.8-expressing CHO cells consisted of two additions of solutions into the plate. The first addition (10 µL) consists of the compound tested for inhibitory activity (crude venom samples, freeze-dried venom fractions, purified peptide, or buffer solution).…”

Section: Transfectionmentioning

confidence: 99%

“…Cells were split every 3-6 days in a ratio of 1:5 using 0.25% trypsin/EDTA. Cells were seeded on T75 cm 2 emission at 515-575 nM. Camera gain and intensity were adjusted for each plate to yield a minimum of 1000-1500 arbitrary fluorescence units (AFU) baseline fluorescence.…”

Section: Transfectionmentioning

confidence: 99%

“…In order to examine the effect of Na V 1.6, GIIIA is administered together with TIIIA, another conotoxin-derived peptide that inhibits Na V 1.1, 1.2, 1.3, and Na V 1.4 212 , but not Na V 1.6. The differential inhibitory activity of the two peptides allows for assessment of the effect of Na V 1.6 inhibition independent of Na V 1.1, Na V 1.2, and Na V 1.4 inhibition in animal models 2,133,200 . An existing peptide with the opposite action to GIIIA is the β-scorpion toxin Cn2, which functions as a potent Na V 1.6-selective activator 202 .…”

Section: Introductionmentioning

confidence: 99%

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A pharmacological and transcriptomic approach to exploring novel pain targets

Yin¹

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Ever since the discovery that mutations in the voltage-gated sodium channel 1.7 protein are responsible for human congenital insensitivity to pain, the voltage-gated sodium channel (Na V ) family of ion channels has been the subject of intense research with the hope of discovering novel analgesics. We now know that Na V 1.7 deletion in select neuronal populations yield different phenotypes, with the deletion of Na V 1.7 in all sensory neurons being successful at abolishing mechanical and heat-induced pain. However, it is rapidly becoming apparent that a number of pain syndromes are not modulated by Na V 1.7 at all, such as oxaliplatin-mediated neuropathy. It is particularly interesting to note that the loss of Na V 1.7 function is also associated with the selective inhibition of pain mediated by specific stimuli, such as that observed in burn-induced pain where Na V 1.7 gene knockout abolished thermal allodynia but did not affect mechanical allodynia. Accordingly, significant interests exist in delineating the contribution of other Na V isoforms in modality-specific pain pathways. Two other isoforms, Na V 1.6 and Na V 1.8, are now specifically implicated in some Na V 1.7-independent conditions such as oxaliplatin-induced cold allodynia. Such selective contributions of specific ion channel isoforms to pain highlight the need to discover other putative protein targets involved in mediating nociception.The aim of my work is therefore to discover selective molecular inhibitors of Na V 1.6 and Na V 1.8, to find useful cell models for peripheral nociceptors, to investigate the roles of Na V 1.6 and Na V 1.8 in an animal model of burn-induced pain, and to screen for putative new targets for analgesia in burn-related pain.Chapter 2 of this thesis describes activity-guided discovery of novel Na V 1.6 and Na V 1.8-modulting peptides from crude spider venoms. Crude venom from Poecilotheria metallica successfully reduced Na V 1.8-mediated voltage changes in HEK293-expressing cells. A new Na V 1.8-inhibitory peptide was sequenced from the venom and named Pme1a. However, Pme1a exhibited TRPV1 agonist activity and induced nocifensive behaviours, such as paw licking, after injection into the hind paws of mice, indicating the peptide was not a selective Na V 1.8 modulator and was unsuitable as a tool for Na V 1.8 investigation.iii With the unsuccessful exploration of spider venoms for new specific inhibitors, I then investigated in vitro cell models as tools to research specific nociceptor subtypes that express Na V 1.6 or Na V 1.8. In Chapter 3, I provide the first complete transcriptome of three common in vitro neuronal cell lines (SH-SY5Y, F-11, and ND7/23) to examine whether they were appropriate for investigating the functions of Na V 1.6 and Na V 1.8, and to identify if the cell lines resemble in vivo dorsal root ganglion (DRG) neuronal subclasses. The three cell lines examined all expressed proteins belonging to similar pathways and of similar proportions to native DRG neurons. However, they did not express any ce...

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Optimizing Nav1.7‐Targeted Analgesics: Revealing Off‐Target Effects of Spider Venom‐Derived Peptide Toxins and Engineering Strategies for Improvement

Luo,

Zhou,

et al. 2024

Advanced Science

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The inhibition of Nav1.7 is a promising strategy for the development of analgesic treatments. Spider venom‐derived peptide toxins are recognized as significant sources of Nav1.7 inhibitors. However, their development has been impeded by limited selectivity. In this study, eight peptide toxins from three distinct spider venom Nav channel families demonstrated robust inhibition of hNav1.7, rKv4.2, and rKv4.3 (rKv4.2/4.3) currents, exhibiting a similar mode of action. The analysis of structure and function relationship revealed a significant overlap in the pharmacophore responsible for inhibiting hNav1.7 and rKv4.2 by HNTX‐III, although Lys25 seems to play a more pivotal role in the inhibition of rKv4.2/4.3. Pharmacophore‐guided rational design is employed for the development of an mGpTx1 analogue, mGpTx1‐SA, which retains its inhibition of hNav1.7 while significantly reducing its inhibition of rKv4.2/4.3 and eliminating cardiotoxicity. Moreover, mGpTx1‐SA demonstrates potent analgesic effects in both inflammatory and neuropathic pain models, accompanied by an improved in vivo safety profile. The results suggest that off‐target inhibition of rKv4.2/4.3 by specific spider peptide toxins targeting hNav1.7 may arise from a conserved binding motif. This insight promises to facilitate the design of hNav1.7‐specific analgesics, aimed at minimizing rKv4.2/4.3 inhibition and associated toxicity, thereby enhancing their suitability for therapeutic applications.

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An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways

Cited by 151 publications

References 58 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

A pharmacological and transcriptomic approach to exploring novel pain targets

Optimizing Nav1.7‐Targeted Analgesics: Revealing Off‐Target Effects of Spider Venom‐Derived Peptide Toxins and Engineering Strategies for Improvement

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