The transient receptor potential vanilloid 4 (TRPV4) is a primary afferent transducer that plays a crucial role in neuropathic
hyperalgesia for osmotic and mechanical stimuli, as well as in inflammatory mediator-induced
hyperalgesia for osmotic stimuli. In view of the clinical importance of
mechanical hyperalgesia in inflammatory states, the present study investigated the role of TRPV4 in
mechanical hyperalgesia induced by inflammatory mediators and the second-messenger pathways involved.
Intradermal injection of either the inflammogen
carrageenan or a soup of inflammatory mediators enhanced the nocifensive paw-withdrawal reflex elicited by hypotonic or mechanical stimuli in rat. Spinal administration of TRPV4 antisense
oligodeoxynucleotide blocked the enhancement without altering baseline nociceptive threshold. Similarly, in TRPV4(-/-) knock-out mice, inflammatory soup failed to induce any significant mechanical or osmotic
hyperalgesia. In vitro investigation showed that inflammatory mediators engage the TRPV4-mediated mechanism of sensitization by direct action on dissociated primary afferent neurons. Additional behavioral observations suggested that multiple mediators are necessary to achieve sufficient activation of the cAMP pathway to engage the TRPV4-dependent mechanism of
hyperalgesia. In addition, direct activation of
protein kinase A or
protein kinase C epsilon, two pathways that mediate
inflammation-induced
mechanical hyperalgesia, also induced
hyperalgesia for both hypotonic and mechanical stimuli that was decreased by TRPV4 antisense and absent in TRPV4(-/-) mice. We conclude that TRPV4 plays a crucial role in the
mechanical hyperalgesia that is generated by the concerted action of inflammatory mediators present in inflamed tissues.