RRC ID 56565
著者 Lopez-Bellido R, Puig S, Huang PJ, Tsai CR, Turner HN, Galko MJ, Gutstein HB.
タイトル Growth Factor Signaling Regulates Mechanical Nociception in Flies and Vertebrates.
ジャーナル J Neurosci
Abstract 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.
巻・号 39(30)
ページ 6012-6030
公開日 2019-7-24
DOI 10.1523/JNEUROSCI.2950-18.2019
PII JNEUROSCI.2950-18.2019
PMID 31138657
PMC PMC6650988
MeSH Animals Animals, Genetically Modified Drosophila melanogaster Intercellular Signaling Peptides and Proteins / genetics Intercellular Signaling Peptides and Proteins / metabolism* Larva Male Nociception / drug effects Nociception / physiology* Physical Stimulation / adverse effects Rats Rats, Sprague-Dawley Sensory Receptor Cells / drug effects Sensory Receptor Cells / metabolism* Signal Transduction / drug effects Signal Transduction / physiology Species Specificity Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors Vascular Endothelial Growth Factor Receptor-2 / genetics Vascular Endothelial Growth Factor Receptor-2 / metabolism* Vertebrates
IF 6.074
引用数 2
リソース情報
ショウジョウバエ 8222R-3 13780R-1 13780R-2 13781R-1