TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization.
The transient receptor potential vanilloid 4 (TRPV4) contributes to mechanical hyperalgesia of diverse etiologies, presumably as part of a mechanoreceptor signaling complex (Alessandri-Haber et al., 2008). To investigate the hypothesis that a functional interaction between TRPV4 and stretch-activated ion channels (SACs) is involved in this mechanical transduction mechanism, we used a selective SACs inhibitor, GsMTx-4. Intradermal injection of GsMTx-4 in the rat hindpaw reversed the mechanical hyperalgesia induced by intradermal injection of inflammatory mediators. In vivo single fiber recordings showed that GsMTx-4 reversed inflammatory mediator-induced decrease in mechanical threshold in half of sensitized C-fibers. Furthermore, GsMTx-4 reduced hyperalgesia to both mechanical and hypotonic stimuli in different models of inflammatory and neuropathic pain, although it had no effect on baseline mechanical nociceptive thresholds. TRPC1 and TRPC6, two GsMTx-4-sensitive SACs, are expressed in dorsal root ganglion (DRG) neurons. Single-cell reverse transcription-PCR showed that messenger RNAs for TRPV4, TRPC1, and TRPC6 are frequently coexpressed in DRG neurons. Spinal intrathecal administration of oligodeoxynucleotides antisense to TRPC1 and TRPC6, like that to TRPV4, reversed the hyperalgesia to mechanical and hypotonic stimuli induced by inflammatory mediators without affecting baseline mechanical nociceptive threshold. However, antisense to TRPC6, but not to TRPC1, reversed the mechanical hyperalgesia induced by a thermal injury or the TRPV4-selective agonist 4alpha-PDD (4 alpha-phorbol 12,13-didecanoate). We conclude that TRPC1 and TRPC6 channels cooperate with TRPV4 channels to mediate mechanical hyperalgesia and primary afferent nociceptor sensitization, although they may have distinctive roles.
Alessandri-Haber
Nicole
N
Department of Oral and Maxillofacial Surgery, University of California, San Francisco, California 94143-0440, USA. nicole.haber@ucsf.edu
Dina
Olayinka A
OA
Chen
Xiaoje
X
Levine
Jon D
JD
D000818:Animals; D005528:Foot; D005727:Ganglia, Spinal / Q000502:physiology*; D015870:Gene Expression; D006614:Hindlimb; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000378:metabolism; D017288:Pain Threshold / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D010703:Phorbol Esters; D010812:Physical Stimulation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013111:Spider Venoms / Q000494:pharmacology; D050052:TRPC Cation Channels / Q000378:metabolism*; D000074287:TRPC6 Cation Channel; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
D036341:Intercellular Signaling Peptides and Proteins; C411249:MTx4 protein, Grammostola spatulata; D020319:Oligodeoxyribonucleotides, Antisense; D010455:Peptides; D010703:Phorbol Esters; D012333:RNA, Messenger; D013111:Spider Venoms; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; D050916:TRPV Cation Channels; C492146:Trpc6 protein, mouse; C492145:Trpc6 protein, rat; C486576:Trpv4 protein, mouse; C096351:transient receptor potential cation channel, subfamily C, member 1; C008876:phorbol-12,13-didecanoate