Sensitization of TRPV1 by EP₁ and IP Reveals Peripheral Nociceptive Mechanism of Prostaglandins

Abstract

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 TRPV1 is a nonselective cation channel expressed in sensory neurons and activated by various noxious stimuli. TRPV1 has been reported to be critical for inflammatory pain mediated through PKA-and PKC-dependent pathways. PGE 2 or PGI 2 increased or sensitized TRPV1 responses through EP 1 or IP receptors, respectively predominantly in a PKC-dependent manner in both HEK293 cells expressing TRPV1 and mouse DRG neurons. In the presence of PGE 2 or PGI 2 , the temperature threshold for TRPV1 activation was reduced below 35°C, so that temperatures near body temperature are sufficient to activate TRPV1.

Prostaglandin facilitates afferent nerve activity via EP1 receptors during urinary bladder inflammation in rats

“…TRPV1 was activated by capsaicin and capsaicin infusion into the urinary bladder was shown to shorten the ICI (5). EP 1 facilitated the effects of capsaicin on DRG neurons (23). Thus, EP 1 receptors could facilitate bladder afferent nerve activity through TRPV1 channels.…”

“…These receptors could be part of mechanosensitive and inflammatory chemical sensitive systems. EP 1 receptor mRNA was found in dorsal root ganglion (DRG) neurons (24), and activation of EP 1 receptors sensitizes C-fiber DRG neurons (23). Thus, EP 1 receptors may localize in the peripheral primary afferent terminals, where they could serve as a key component for the activation of afferent discharge during AA-induced inflammation of the bladder.…”

Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1

“…Thus, prostanoids activate neuronal PG receptors, mainly of the EP subtype, that couple to downstream mediators including cAMP and protein kinases A and C (28, 29), which activate voltage-dependent sodium channels (30), or inhibit voltage-dependent potassium channels (31), inducing neuronal hypersensitivity. Prostanoids similarly sensitize other channels on sensory neurons to cause hyperalgesia, as is the case for TRPV1, where PGs lowered the threshold temperature for channel activation (32). There is no evidence that PGs cause pain by direct stimulation of nociceptors (7-9).…”

Impaired Nociception and Inflammatory Pain Sensation in Mice Lacking the Prokineticin Receptor PKR1: Focus on Interaction between PKR1 and the Capsaicin Receptor TRPV1 in Pain Behavior

“…These signaling pathways appear to involve phosphorylation by kinases including protein kinase A (PKA), PKC, Ca 2ϩ /CaM-dependent kinase II or Src kinase and phosphatidylinositol 3-kinase (Zhuang et al, 2004). Prostaglandins released in response to tissue injury and inflammation sensitize TRPV1 by activating their G-protein-coupled prostanoid receptors EP1 and IP (Moriyama et al, 2005) through a PKA-dependent pathway (Pitchford and Levine, 1991;Lopshire and Nicol, 1998;Rathee et al, 2002). Activation of the group I metabotropic glutamate receptors mGlu1 and mGlu5 potentiates capsaicin responses in mouse sensory neurons by the phospholipase C-prostanoid-PKA pathway (Hu et al, 2002).…”