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.