Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins

Prostaglandin E-2 (PGE(2)) and prostaglandin I-2 (PGI(2)) are major inflammatory mediators that play important roles in pain sensation and hyperalgesia. The role of their receptors (EP and IP, respectively) in inflammation has been well documented, although the EP receptor subtypes involved in this process and the underlying cellular mechanisms remain to be elucidated. The capsaicin receptor TRPVI is a nonselective cation channel expressed in sensory neurons and activated by various noxious stimuli. TRPVI has been reported to be critical for inflammatory pain mediated through PKA- and PKC-dependent pathways. PGE(2) or PGI(2-)increased or sensitized TRPVI responses through EP1 or IP receptors, respectively predominantly in a PKC- dependent manner in both HEK293 cells expressing TRPVI and mouse DRG neurons. In the presence of PGE(2) or PGI(2), the temperature threshold for TRPVI activation was reduced below 35 degrees C, so that temperatures near body temperature are sufficient to activate TRPVI. A PKA- dependent pathway was also involved in the potentiation of TRPVI through EP4 and IP receptors upon exposure to PGE(2) and PGI(2), respectively. Both PGE(2)- induced thermal hyperalgesia and inflammatory nociceptive responses were diminished in TRPVI-deficient mice and EP1-deficient mice. IP receptor involvement was also demonstrated using TRPVI-deficient mice and IP-deficient mice. Thus, the potentiation or sensitization of TRPVI activity through EP1 or IP activation might be one important mechanism underlying the peripheral nociceptive actions of PGE(2) or PGI(2).