Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice

Rivat, Cyril; Sar, Chamroeun; Méchaly, Ilana; Leyris, Jean-Philippe; Diouloufet, Lucie; Sonrier, Corinne; Philipson, Yann; Lucas, Olivier; Mallié, Sylvie; Jouvenel, Antoine; Tassou, Adrien; Haton, Henri; Ventéo, Stéphanie; Pin, Jean‐Philippe; Trinquet, Eric; Charrier‐Savournin, Fabienne; Mezghrani, Alexandre; Joly, Willy; Mion, Julie; Schmitt, Martine; Pattyn, Alexandre; Marmigère, Frédéric; Sokoloff, Pierre; Carroll, Patrick; Rognan, Didier; Valmier, Jean

doi:10.1038/s41467-018-03496-2

Cited by 54 publications

(64 citation statements)

References 66 publications

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“…PDGF peptides can bind with extremely high affinity to the VEGFR-2, and computational predictions suggest that PDGF peptides may account for a large percentage of VEGFR-2 binding in vivo (Mamer et al, 2017). Also, the Flt3 RTK can alter mechanical sensitivity in a TRP channel-dependent manner (Rivat et al, 2018), further supporting the concept that RTKs may regulate mechanical nociception. Further studies are indicated to better understand how RTKs, piezo, and TRP channels might interact to regulate mechanical sensitivity in vertebrates.…”

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confidence: 87%

Growth Factor Signaling Regulates Mechanical Nociception in Flies and Vertebrates

et al. 2019

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Mechanical sensitization is one of the most difficult clinical pain problems to treat. However, the molecular and genetic bases of mechanical nociception are unclear. Here we develop a Drosophila model of mechanical nociception to investigate the ion channels and signaling pathways that regulate mechanical nociception. We fabricated von Frey filaments that span the subthreshold to high noxious range for Drosophila larvae. Using these, we discovered that pressure (force/area), rather than force per se, is the main determinant of aversive rolling responses to noxious mechanical stimuli. We demonstrated that the RTK PDGF/VEGF receptor (Pvr) and its ligands (Pvfs 2 and 3) are required for mechanical nociception and normal dendritic branching. Pvr is expressed and functions in class IV sensory neurons, whereas Pvf2 and Pvf3 are produced by multiple tissues. Constitutive overexpression of Pvr and its ligands or inducible overexpression of Pvr led to mechanical hypersensitivity that could be partially separated from morphological effects. Genetic analyses revealed that the Piezo and Pain ion channels are required for mechanical hypersensitivity observed upon ectopic activation of Pvr signaling. PDGF, but not VEGF, peptides caused mechanical hypersensitivity in rats. Pharmacological inhibition of VEGF receptor Type 2 (VEGFR-2) signaling attenuated mechanical nociception in rats, suggesting a conserved role for PDGF and VEGFR-2 signaling in regulating mechanical nociception. VEGFR-2 inhibition also attenuated morphine analgesic tolerance in rats. Our results reveal that a conserved RTK signaling pathway regulates baseline mechanical nociception in flies and rats. Significance StatementHypersensitivity to touch is poorly understood and extremely difficult to treat. Using a refined Drosophila model of mechanical nociception, we discovered a conserved VEGF-related receptor tyrosine kinase signaling pathway that regulates mechanical nociception in flies. Importantly, pharmacological inhibition of VEGF receptor Type 2 signaling in rats causes analgesia and blocks opioid tolerance. We have thus established a robust, genetically tractable system for the rapid identification and functional analysis of conserved genes underlying mechanical pain sensitivity.

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confidence: 87%

Growth Factor Signaling Regulates Mechanical Nociception in Flies and Vertebrates

et al. 2019

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“…Therefore, the test can be utilized to elucidate the potential mechanism of tested drugs. CNS acting compounds act on both phases; however, many anti-inflammatory drugs inhibit only the chronic phase [24,25].…”

Section: Discussionmentioning

confidence: 99%

Methanol extract of smokeless tobacco alters inflammation and nociception process in animal models

Abdelwahab¹,

Mohan²,

Taha³

et al. 2019

Trop. J. Pharm Res

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Purpose: To investigate the inflammatory and nociceptive alterations due to the use of Nicotiana tabacum or smokeless tobacco (MEST) owing to the fact that it is used by some people to relieve dental pain. Methods: Hepatic biochemical indicators and thiobarbituric acid reactive substances assay were used to assess MEST toxicity and pharmacological doses selection. The effects on inflammation of different pharmacological doses (100, 200 and 500 mg/kg i.p.) of MEST were evaluated using xylene-induced ear edema and cotton pellet granuloma tests. Indomethacin (10 mg/kg, i.p.) was used as positive standard drug, whereas the vehicle 0.5 % CMC treated group was considered as negative control. Acetic acid-induced abdominal contraction test and formalin-induced hind paw licking model were utilized to assess the role of MEST in nociception. Indomethacin (10 mg/kg i.p.) and diclofenac sodium (10 mg/kg i.p.) were used as positives standard drugs. The vehicle used was 0.5% CMC which served as the negative control. Results: MEST (50 %, 200 mg/kg) and indomethacin (47.5 %) both elicited a significant (p < 0.001) anti-edematogenic effect on xylene-induced ear edema. MEST also showed a significant (p < 0.001) inhibitory effect on granuloma formation at all administered doses as compared to the untreated groups which was comparable to standard drug indomethacin. The number of acetic acid induced writhings was observed to be significantly increased (p < 0.001) by MEST at all doses, unlike diclofenac that led to significant reduction (p < 0.001) in the number of writhings, when compared to the untreated group. MEST also showed a significant (p < 0.05) dose-dependent reduction of the hind paw licking caused by formalin when compared to the vehicle control. Conclusion: These results signify that administration of MEST induces inflammatory and nociceptive alterations. However, the extract is not recommended for dental pain due to its other toxic effects that have previously been reported.

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“…The sections were washed 3 times, slidemounted, and coverslipped in mounting medium with the nuclear stain DAPI (Vector Laboratories). Anti-Tuj1 antibody has previously been used for the detection of DRG neurons (Rivat et al, 2018). Anti-Tuj1 antibody reacts with a structural protein that is a component of tubulin, whereas anti-NeuN antibody stains the nuclei of neurons.…”

Section: Methodsmentioning

confidence: 99%

Increased Expression of Fibronectin Leucine-Rich Transmembrane Protein 3 in the Dorsal Root Ganglion Induces Neuropathic Pain in Rats

et al. 2019

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Neuropathic pain is a chronic condition that occurs frequently after nerve injury and induces hypersensitivity or allodynia characterized by aberrant neuronal excitability in the spinal cord dorsal horn. Fibronectin leucine-rich transmembrane protein 3 (FLRT3) is a modulator of neurite outgrowth, axon pathfinding, and cell adhesion, which is upregulated in the dorsal horn following peripheral nerve injury. However, the function of FLRT3 in adults remains unknown. Therefore, we aimed to investigate the involvement of spinal FLRT3 in neuropathic pain using rodent models. In the dorsal horns of male rats, FLRT3 protein levels increased at day 4 after peripheral nerve injury. In the DRG, FLRT3 was expressed in activating transcription factor 3-positive, injured sensory neurons. Peripheral nerve injury stimulated Flrt3 transcription in the DRG but not in the spinal cord. Intrathecal administration of FLRT3 protein to naive rats induced mechanical allodynia and GluN2B phosphorylation in the spinal cord. DRG-specific FLRT3 overexpression using adeno-associated virus also produced mechanical allodynia. Conversely, a function-blocking FLRT3 antibody attenuated mechanical allodynia after partial sciatic nerve ligation. Therefore, FLRT3 derived from injured DRG neurons increases dorsal horn excitability and induces mechanical allodynia.

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Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice

Cited by 54 publications

References 66 publications

Growth Factor Signaling Regulates Mechanical Nociception in Flies and Vertebrates

Growth Factor Signaling Regulates Mechanical Nociception in Flies and Vertebrates

Methanol extract of smokeless tobacco alters inflammation and nociception process in animal models

Increased Expression of Fibronectin Leucine-Rich Transmembrane Protein 3 in the Dorsal Root Ganglion Induces Neuropathic Pain in Rats

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