Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat.
The development of treatments for neuropathic pain has been hindered by our limited understanding of the basic mechanisms underlying abnormalities in nociceptor hyperexcitability. We recently showed that the polymodal receptor transient receptor potential vanilloid 4 (TRPV4), a member of the transient receptor potential (TRP) family of ion channels, may play a role in inflammatory pain (Alessandri-Haber et al., 2003). The present study tested whether TRVP4 also contributes to neuropathic pain, using a rat model of Taxol-induced painful peripheral neuropathy. Taxol is the most widely used drug for the treatment of a variety of tumor types, but the dose of Taxol that can be tolerated is limited by the development of a small-fiber painful peripheral neuropathy. We found that Taxol treatment enhanced the nociceptive behavioral responses to both mechanical and hypotonic stimulation of the hind paw. Spinal administration of antisense oligodeoxynucleotides to TRPV4, which reduced the expression of TRPV4 in sensory nerve, abolished Taxol-induced mechanical hyperalgesia and attenuated hypotonic hyperalgesia by 42%. The enhancement of osmotic nociception involves sensitization of osmotransduction in primary afferents because osmotransduction was enhanced in cultured sensory neurons isolated from Taxol-treated rats. Taxol-induced TRPV4-mediated hyperalgesia and the enhanced osmotransduction in cultured nociceptors were dependent on integrin/Src tyrosine kinase signaling. These results suggest that TRPV4 plays a crucial role in a painful peripheral neuropathy, making it a very promising target for the development of a novel class of analgesics.
Alessandri-Haber
Nicole
N
Division of Neurosciences, University of California San Francisco, San Francisco, California 94143-0440, USA.
Dina
Olayinka A
OA
Yeh
Jenny J
JJ
Parada
Carlos A
CA
Reichling
David B
DB
Levine
Jon D
JD
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D007038:Hypotonic Solutions; D016023:Integrins / Q000378:metabolism; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D009619:Nociceptors / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D017239:Paclitaxel; D010147:Pain Measurement; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D050916:TRPV Cation Channels; D019061:src-Family Kinases / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D027682:Cation Transport Proteins; D007038:Hypotonic Solutions; D016023:Integrins; D007473:Ion Channels; D016376:Oligonucleotides, Antisense; D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat; D019061:src-Family Kinases; D017239:Paclitaxel; D002118:Calcium