Growth Factor Signaling Regulates Mechanical Nociception in Flies and Vertebrates
| Autor: | Howard B. Gutstein, Heather N. Turner, Michael J. Galko, Chang Ru Tsai, Patrick J. Huang, Roger López-Bellido, Stephanie Puig |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Nociception 0301 basic medicine Sensory Receptor Cells medicine.medical_treatment Sensory system Receptor tyrosine kinase Animals Genetically Modified Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Species Specificity Physical Stimulation medicine Animals Research Articles Ion channel Sensitization biology Chemistry General Neuroscience Growth factor Vascular Endothelial Growth Factor Receptor-2 Rats Cell biology Drosophila melanogaster 030104 developmental biology medicine.anatomical_structure Larva Vertebrates Morphine biology.protein Intercellular Signaling Peptides and Proteins Signal transduction 030217 neurology & neurosurgery Platelet-derived growth factor receptor Signal Transduction medicine.drug |
| Zdroj: | The Journal of Neuroscience. 39:6012-6030 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.2950-18.2019 |
| Popis: | 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 STATEMENT Hypersensitivity 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. |
| Databáze: | OpenAIRE |
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