Contribution of Piezo2 to endothelium-dependent pain.
BACKGROUND
We evaluated the role of a mechanically-gated ion channel, Piezo2, in mechanical stimulation-induced enhancement of hyperalgesia produced by the pronociceptive vasoactive mediator endothelin-1, an innocuous mechanical stimulus-induced enhancement of hyperalgesia that is vascular endothelial cell dependent. We also evaluated its role in a preclinical model of a vascular endothelial cell dependent painful peripheral neuropathy.


RESULTS
The local administration of oligodeoxynucleotides antisense to Piezo2 mRNA, at the site of nociceptive testing in the rat's hind paw, but not intrathecally at the central terminal of the nociceptor, prevented innocuous stimulus-induced enhancement of hyperalgesia produced by endothelin-1 (100 ng). The mechanical hyperalgesia induced by oxaliplatin (2 mg/kg. i.v.), which was inhibited by impairing endothelial cell function, was similarly attenuated by local injection of the Piezo2 antisense. Polymerase chain reaction analysis demonstrated for the first time the presence of Piezo2 mRNA in endothelial cells.


CONCLUSIONS
These results support the hypothesis that Piezo2 is a mechano-transducer in the endothelial cell where it contributes to stimulus-dependent hyperalgesia, and a model of chemotherapy-induced painful peripheral neuropathy.
Division of Neuroscience, Department of Medicine, University of California, San Francisco, 521 Parnassus Avenue, San Francisco, CA, 94143-0440, USA. Luiz.Ferrari@ucsf.edu.
Luiz F
LF
Ferrari
Division of Neuroscience, Department of Medicine, University of California, San Francisco, 521 Parnassus Avenue, San Francisco, CA, 94143-0440, USA. Oliver.Bogen@ucsf.edu.
Oliver
O
Bogen
Division of Neuroscience, Department of Medicine, University of California, San Francisco, 521 Parnassus Avenue, San Francisco, CA, 94143-0440, USA. Paul.Green@ucsf.edu.
Paul
P
Green
Division of Neuroscience, Department of Medicine, University of California, San Francisco, 521 Parnassus Avenue, San Francisco, CA, 94143-0440, USA. jon.levine@ucsf.edu.
Jon D
JD
Levine
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D019332:Endothelin-1 / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014110:Touch
D000970:Antineoplastic Agents; D019332:Endothelin-1; D007473:Ion Channels; D016376:Oligonucleotides, Antisense; D009944:Organoplatinum Compounds; C000589204:piezo2 protein, rat; D000077150:Oxaliplatin