- Open Access
Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins
- Tomoko Moriyama†1, 2,
- Tomohiro Higashi†2, 3,
- Kazuya Togashi2, 3,
- Tohko Iida1,
- Eri Segi4,
- Yukihiko Sugimoto5,
- Tomoko Tominaga2, 3,
- Shuh Narumiya4 and
- Makoto Tominaga1, 2, 3Email author
© Moriyama et al; licensee BioMed Central Ltd. 2005
Received: 06 January 2005
Accepted: 17 January 2005
Published: 17 January 2005
Prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2) 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. PGE2 or PGI2increased or sensitized TRPV1 responses through EP1 or IP receptors, respectively predominantly in a PKC-dependent manner in both HEK293 cells expressing TRPV1 and mouse DRG neurons. In the presence of PGE2 or PGI2, the temperature threshold for TRPV1 activation was reduced below 35°C, so that temperatures near body temperature are sufficient to activate TRPV1. A PKA-dependent pathway was also involved in the potentiation of TRPV1 through EP4 and IP receptors upon exposure to PGE2 and PGI2, respectively. Both PGE2-induced thermal hyperalgesia and inflammatory nociceptive responses were diminished in TRPV1-deficient mice and EP1-deficient mice. IP receptor involvement was also demonstrated using TRPV1-deficient mice and IP-deficient mice. Thus, the potentiation or sensitization of TRPV1 activity through EP1 or IP activation might be one important mechanism underlying the peripheral nociceptive actions of PGE2 or PGI2.
Tissue damage and inflammation produce an array of chemical mediators such as ATP, bradykinin, prostanoids, protons, cytokines and peptides including substance P that can excite or sensitize nociceptors to elicit pain at the site of injury. Among them prostanoids were shown to influence inflammation, and their administration was found to reproduce the major signs of inflammation including augmented pain . Prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2) are the products of arachidonic acid metabolism through the cyclooxygenase pathway. In addition to numerous other physiological actions in vivo, previous studies have indicated important roles for PGE2 in nociception and inflammation [2, 3]. PGE2 is generated in most cells in response to mechanical, thermal or chemical injury and inflammatory insult, resulting in sensitization or direct activation of nearby sensory nerve endings. Analgesic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are attributed predominantly to inhibition of prostaglandin synthesis. Prostaglandins act upon a family of pharmacologically distinct prostanoid receptors including EP1, EP2, EP3, EP4 and IP that activate several different G protein-coupled signaling pathways [2, 4, 5]. Primary sensory neurons in dorsal root ganglion (DRG) are known to express mRNAs encoding several prostanoid receptor subtypes, IP, EP1, EP3 and EP4 [6, 7]. The role of IP in inflammation has been clearly shown by the analysis of IP-deficient mice, although the underlying cellular mechanisms still remain to be elucidated . In contrast, the potential involvement of EP receptors other than IP in inflammation and pain generation has not been well studied, although some earlier studies have suggested that prostanoids contribute to the development of pain through EP receptors [9, 10].
The capsaicin receptor TRPV1 is a non-selective cation channel expressed predominantly in unmyelinated C-fibers . TRPV1 is activated not only by capsaicin, but also by protons or heat (with a threshold > ~43°C), both of which cause pain in vivo [11–13]. A prominent role of TRPV1 in nociception has been demonstrated in studies of TRPV1-deficient mice [14, 15].
Recently, we reported that inflammatory mediators such as ATP, bradykinin and trypsin or tryptase potentiate TRPV1 activity in a PKC-dependent manner [16–18], and identified two target serine residues in TRPV1 as substrates for PKC-dependent phosphorylation . On the other hand, there are several reports showing that a PKA signaling pathway mediates PGE2-induced potentiation of capsaicin-evoked responses in rat sensory neurons [20–22]. Therefore, we examined the effects of PGE2 and PGI2 on TRPV1 activity. Surprisingly, we found the functional interaction of TRPV1 with PGE2 or PGI2 occurs mainly through a PKC-dependent pathway at both cellular and behavioral levels.
Functional interaction between TRPV1 and PGE2
PGE2 increases TRPV1 activity through EP1 receptors
The signaling pathway downstream of EP1 remains to be clarified. We have reported that Gq/11-coupled metabotropic receptor activation such as ATP (P2Y), bradykinin (B2) and proteinase-activated receptor 2 (PAR2) receptors causes potentiation or sensitization of TRPV1 through the PKC-dependent phosphorylation of TRPV1 [16–18, 25]. Therefore, we examined whether a similar signal transduction pathway is involved in the regulation of TRPV1 responses through EP1. When calphostin C (Calp.C), a specific PKC inhibitor, was added to the pipette solution, the effect of PGE2 was almost completely inhibited (0.92 ± 0.15 fold increase, n = 10) (Figure 2F). Similarly, a PKCε translocation inhibitor (PKCε-I) abolished the potentiation of TRPV1 response by PGE2 (1.11 ± 0.25 fold increase, n = 11) (Figure 2F). These data suggest that PGE2-induced potentiation of TRPV1 responsiveness develops through activation of PKCε. To further confirm the involvement of PKC-dependent phosphorylation, PGE2 effects were examined using cells expressing a TRPV1 mutant, S502A/S800A which is insensitive to PKC-dependent phosphorylation . No potentiation of capsaicin-activated currents was observed upon PGE2treatment of cells expressing S502A/S800A (0.85 ± 0.15 fold increase, n = 5) (Figure 2F), further indicating the involvement of PKC-dependent phosphorylation. Since S502 is a PKA-phosphorylation site as well , we examined the effects of treatment with a mixture of FSK, IBMX and dbcAMP on the capsaicin-activated currents in cells expressing S502A/S800A. Such treatment failed to potentiate the capsaicin-activated currents (1.13 ± 0.07 fold increase, n = 10), suggesting that S502 is a substrate for PKA-dependent phosphorylation of TRPV1 as well.
Sensitization of TRPV1 by EP1 receptors in mouse
Sensitization of TRPV1 by IP receptors
The data presented herein demonstrate that TRPV1 is essential for the development of thermal hyperalgesia in vivo induced by two major inflammation-associated prostaglandins, PGE2 and PGI2, and that TRPV1 and EP1 or IP receptors can functionally interact, mainly through a PKC-dependent pathway. The temperature threshold for TRPV1 activation is reduced below 35°C in the presence of prostaglandins, so that TRPV1 can be activated at normal body temperature, possibly leading to spontaneous pain sensation. This interaction might be one important underlying mechanism for the well-recognized peripheral nociceptive actions of PGE2 or PGI2 in the context of inflammation. In the present study, 1 μM PGE2 or PGI2 was found to potentiate or sensitize TRPV1 activity. It is not well known how much PGE2 or PGI2 is released locally at the site of inflammation. However, more than micromolar-order concentrations of PGE2 and PGI2 have been reported to be synthesized by macrophages upon lipopolysacharide (LPS) stimulation [33, 34], suggesting that 1 μM is an attainable concentration in the context of inflammation. It has been previously reported that EP1 is coupled to intracellular Ca2+ mobilization in CHO cells . However, the transduction events downstream of EP1 signaling have been unclear. Together with a report suggesting the possible coupling of EP1 with Gq/11-protein , our data indicate that EP1 receptors activate a PKC-dependent signal transduction pathway.
There has been extensive work demonstrating the activation of a PKA-dependent pathway by PGE2 that influences capsaicin- or heat-mediated actions in rat sensory neurons [20–22, 37, 38] as well as interactions between cloned TRPV1 and PKA [26, 39–42]. These results suggest that PKA plays a pivotal role in the development of hyperalgesia and inflammation by prostaglandins. In our experiments using mouse DRG neurons and HEK293 cells expressing TRPV1, a PKC-dependent pathway was found to be predominantly involved in both PGE2 (1.5 min)- and PGI2 (1.5 min)-induced responses. The reason that there has been no study describing the involvement of a PKC-dependent pathway in the regulation of TRPV1 following prostaglandin receptor activation is not clear. In the present study, it was found that both PKA- and PKC-dependent pathways are involved downstream of prostaglandin actions on TRPV1 although the PKC-dependent one appears to predominate. A PKA-dependent pathway took a relatively long time to exert its potentiating effects on TRPV1 activity, suggesting some difference between PKA- and PKC-dependent phosphorylation of TRPV1. Indeed, Bhave et al. treated cells with 8-Br-cAMP for 30 min to inhibit TRPV1 desensitization through phosphorylation , and significant potentiation of capsaicin-activated currents in rat DRG neurons was observed upon prolonged (greater than 10 min) exposure to PGE2 . Furthermore, there is a report describing the ineffectiveness of PKA stimulation on TRPV1 currents in Xenopus oocytes treated with 8-Br-cAMP and IBMX for relatively short periods . Both PKA-dependent and PKC-dependent pathways might work in concert in native cells. Patch-clamp recordings in the previous studies were performed in the Ca2+-containing solutions, whereas we did all of our experiments under Ca2+-free conditions, to avoid Ca2+-dependent TRPV1 desensitization . Potentiation of capsaicin-activated currents by PGE2 was observed in embryonic rat DRG neurons  while we used adult mouse DRG neurons. Furthermore, potentiation of heat-activated currents , inhibition of desensitization of capsaicin-activated currents [39, 41, 44] or anandamide-induced cytosolic Ca2+ increase  but not potentiation of capsaicin-activated current response were examined in the previous studies investigating the involvement of PKA-dependent pathway in TRPV1 activity. Thus, difference in experimental conditions or readout might also account for the different outcomes. The physiological relevance of the two different pathways downstream of prostaglandin exposure remains to be elucidated. The fact that only PKC activation leads to the reduction of temperature threshold for TRPV1 activation might be pertinent to this issue. Disruption of interaction between phosphatidylinositol-4, 5-bisphosphate (PIP2) and TRPV1 has also been reported to be involved in the sensitization of TRPV1 downstream of PLC activation [45, 46]. In our study, however, both PGE2- and PGI2-induced potentiation of TRPV1 activity was completely inhibited by treatments with two kinds of PKC inhibitors. Thus, we believe that a PKC-dependent pathway is predominantly involved in the PGE2- and PGI2-induced potentiation or sensitization of TRPV1 activity in mice.
The inhibition of PGE2-induced thermal hyperalgesia observed in EP1 -/- mice, while significant, was not very robust, compared with that in TRPV1-/- mice (Figure 4). Other pathways, most likely including one involving PKA, might account for the residual component. Further, inhibition of mustard oil-induced thermal hyperalgesia observed in TRPV1-/- or EP1 -/- mice might seem not to be robust or dramatic (Figure 4). Since many inflammatory factors activating PLC-coupled receptors are involved in the inflammatory response [47, 48]. In such a complicated environment, thermal hyperalgesia was significantly diminished in TRPV1-/- mice or EP1 -/- mice albeit at a few time points, suggesting the importance of the two molecules in the context of inflammatory pain sensation. Given the fact that one of the final targets of both PGE2 and PGI2 is TRPV1 as shown in our study, compounds acting on EP1, IP or TRPV1, or interfering with their interaction could prove useful in the treatment of pain and inflammation.
Potentiation or sensitization of TRPV1 activity through EP1 or IP activation, mainly through PKC- and PKA-dependent mechanisms, might be important mechanism underlying the peripheral nociceptive actions of PGE2 or PGI2.
Male C57BL/6-strain mice (4 weeks, SLC, Shizuoka, Japan), EP1-deficient mice (4 weeks, from Dr. Narumiya), IP-deficient mice (4 weeks, from Dr. Narumiya) or TRPV1-deficient mice (4 weeks, from Dr. Julius, UCSF) were used. They were housed in a controlled environment (12 h light/dark cycle, room temperature 22–24°C, 50–60% relative humidity) with free access to food and water. All procedures involving the care and use of mice were carried out in accordance with institutional (Mie University) guidelines and the National Institute of Health guide for the care and use of laboratory animals.
Thermal nociceptive threshold was assessed using the paw withdrawal test. Mice were placed in a transparent Perspex box on a thin glass platform (Plantar test, Ugo Basile, Italy). They were injected intraplantarly with PGE2 (500 pmol/ 20 μL, Sigma) with or without ONO-8713 (500 pmol/ 20 μL), or with PGI2 (500 pmol/ 20 μL, Sigma), or applied topically to the plantar surface of right hind paw with 10% mustard oil (Sigma) (diluted with mineral oil), and the paw withdrawal latency to radiant heat applied to the plantar surface of hind paw was measured as the time from onset of the radiant heat to the withdrawal of the mouse hind paw.
Human embryonic kidney-derived (HEK293) cells were maintained in Dulbecco's modified Eagle's medium (Invitrogen; supplemented with 10% fetal bovine serum, penicillin, streptomycin and L-glutamine) and transfected with 0.5 μg of rat TRPV1 cDNA and 0.5 μg of mouse EP or IP receptor cDNAs (EP1, EP2, EP3α, EP3β, EP3γ, EP4 or IP) using Lipofectamine Plus Reagent (Invitrogen). Primary cultures prepared from adult C57BL/6-strain mice, EP1-deficient mice or IP-deficient mice dorsal root ganglion (DRG) neurons were incubated in medium containing nerve growth factor (Sigma, 100 ng/ml).
Whole-cell patch-clamp recordings were performed 1 day after transfection to HEK293 cells or dissociation of the DRG neurons. Standard bath solution contained 140 mM NaCl, 5 mM KCl, 2 mM MgCl2, 5 mM EGTA, 10 mM HEPES, 10 mM glucose, pH7.4 (adjusted with NaOH). Pipette solution contained 140 mM KCl, 5 mM EGTA, 10 mM HEPES, pH7.4 (adjusted with KOH). All patch-clamp experiments were performed at room temperature (22°C). Thermal stimulation was applied by increasing the bath temperature at a rate of 1.0°C/sec with a preheated solution. When the heat-activated currents started to inactivate, the preheated solution was changed to a 22°C one. Chamber temperature was monitored with a thermocouple placed within 100 μm of the patch-clamped cell. For this analysis, heat-evoked current responses were compared between different cells, rather than within the same cell, because repetitive heat-evoked currents show significant desensitization even in the absence of extracellular Ca2+  and because the thermal sensitivity of TRPV1 increases with repeated heat application . Threshold temperature for activation was defined as the intersection where two lines approximating the stable baseline current and the clearly increasing temperature-dependent current cross in the temperature-response profile. The sensitivity of DRG neurons to capsaicin is slightly lower than that of TRPV1-transfected HEK293 cells as previously reported [18, 50]. Therefore, we applied capsaicin at 100 nM to DRG neurons and at 20 nM to HEK293 cells.
Intracellular cAMP level was examined using 'cAMP Biotrak Enzymeimmunoassay System' according to the manufacture's direction (Amersham Biosciences). In brief, intracellular cAMP released upon membrane hydrolysis of treated cells (10,000 cells/ well) after stimulation (90 sec) was measured based on competition between unlabelled cAMP and a fix quantity of Peroxidase-labeled cAMP for a limited number of the binding sites on a cAMP specific antibody.
DRG was removed from male C57BL/6-strain mice and frozen in liquid nitrogen, and the frozen tissue was cut on a cryostat at a 10 μm thickness. The sections were incubated with the rabbit anti-rat TRPV1 polyclonal antibody (1: 500; Oncogene) and anti-rat PKCε monoclonal antibody (1: 250; Transduction lab) at 4°C for 2 days. Slides with the section were washed with PBS, followed by incubation with Alexa 488-conjugated goat anti-rabbit IgG (1: 700, Molecular Probes), Alexa 350-conjugated anti-mouse IgG (1: 500, Molecular Probes) and Texas Red-phalloidin (1: 500, Molecular Probes). Images were obtained using an Olympus fluorescent microscope with a cooled-CCD camera (ORCA-ER, Hamamatsu Photonics) and IP-Lab Image software (Scanalytics Inc.).
ONO-DI-004, ONO-8713 and ONO-54918-07 were obtained from Ono Pharmaceutical Co., Ltd (Osaka, Japan). Calphostin C, phorbol 12-myristate 13-acetate, forskolin, 3-isobutyl-1-methylxanthine, dibutyryl-cAMP, isoproterenol, U73122 and U73343 were from Sigma, and PKCε translocation inhibitor was from Calbiochem.
Values are shown as the mean ± S.E. and data are analyzed using an unpaired t test. P values of < 0.05 were considered significant.
We thank D. Julius (University of California, San Francisco) for giving us TRPV1-deficient mice, and M.J. Caterina (Johns Hopkins University), N. Saito (Kobe University) and M. Numazaki (University of Tsukuba) for their critical reading of the manuscript, and N. Suzuki and H. Tsumura (Mie University) for their support for maintaining mice. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan, Japan Brain Foundation, Yamanouchi Foundation for Research on Metabolic Disorders, Uehara Memorial Foundation, AstraZeneca Research Foundation and ONO Medical Research Foundation to M.T.
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