TRPV4 mediates pain-related behavior induced by mild hypertonic stimuli in the presence of inflammatory mediator.
The ligand-gated ion channel, TRPV4, functions as a transducer of hypotonic stimuli in primary afferent nociceptive neurons and contributes to inflammatory and neuropathic pain. Hypertonic saline also stimulates primary afferent nociceptors and the injection of mild hypertonic saline (2-5%) is widely used as an experimental model of pain in humans. Therefore, we tested whether TRPV4 participates in the transduction of hypertonic stimuli. Intradermal injection of 2% (607 mOsm) or 10% (3,250 mOsm) saline solution in the hind paw of rats induced a concentration-dependent pain-related behavior, flinching. Sensitization with prostaglandin E(2) (PGE(2)) caused a 7-fold increase in the number of flinches induced by 2% saline but failed to increase those caused by 10% saline. Spinal administration of antisense oligodeoxynucleotides to TRPV4 caused a 46% decrease in the number of flinches induced by 2% saline, but there was no change in flinching induced by 10% saline. Similarly, only the nociceptive behavior caused by 2% saline was reduced in TRPV4(-/-) knockout mice. The TRPV4-mediated nociceptive behaviors induced by hyper- and hypotonic stimuli were dependent on Src tyrosine kinase. We suggest TRPV4 is a transducer in primary afferents that mediates nociceptive behavior induced by small increases or decreases in osmolarity. Such changes in osmolarity might contribute to pain in inflammatory and neuropathic states.
Alessandri-Haber
Nicole
N
Division of Neurosciences, University of California, 521 Parnassus Avenue, Room C-522, Box 0440, San Francisco, CA 94143-0440, USA.
Joseph
Elizabeth
E
Dina
Olayinka A
OA
Liedtke
Wolfgang
W
Levine
Jon D
JD
D000818:Animals; D006982:Hypertonic Solutions / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000209:etiology / Q000503:physiopathology*; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D009997:Osmotic Pressure / Q000187:drug effects; D010146:Pain / Q000503:physiopathology*; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000187:drug effects / Q000502:physiology*
D006982:Hypertonic Solutions; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; C486577:Trpv4 protein, rat