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Trigeminal Nociceptors Express Prostaglandin Receptors
A.M. Patwardhan1,
J. Vela2,
J. Farugia1,2,
K. Vela1 and
K.M. Hargreaves1,2,*
1 Departments of Endodontics and
2 Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX-78229, USA
Correspondence: * corresponding author, Hargreaves{at}uthscsa.edu
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ABSTRACT
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Orofacial inflammation is associated with prostaglandin release and the sensitization of nociceptive receptors such as the transient receptor potential subtype V1 (TRPV1). We hypothesized that certain PGE2 receptor subtypes (EP1–EP4) are co-expressed with TRPV1 in trigeminal nociceptors and sensitize responses to a TRPV1 agonist, capsaicin. Accordingly, combined in situ hybridization was performed with immunohistochemistry on rat trigeminal ganglia. We next evaluated the effects of specific EP2 and EP3 agonists (butaprost and sulprostone) in cultured trigeminal ganglia neurons. The results showed that EP2 and EP3 are expressed in trigeminal neurons (58% and 53% of total neurons, respectively) and are co-expressed in TRPV1-positive neurons (64% and 67 % of TRPV1-positive neurons, respectively). Moreover, most of the cells expressing EP2 or EP3 mRNA were of small to medium diameter (< 30 µm). The application of butaprost and sulprostone triggered neuropeptide exocytosis, and butaprost sensitized capsaicin responses. Analysis of these data, collectively, supports the hypothesis that prostaglandins regulate trigeminal TRPV1 nociceptors via activation of the EP2 and EP3 receptors.
Key Words: TRPV1 • PGE2 • trigeminal • CGRP
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INTRODUCTION
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The non-steroidal anti-inflammatory drugs (NSAIDs) constitute an effective class of analgesics for the treatment of acute orofacial pain. NSAIDs are thought to exert their analgesic effect primarily via the inhibition of prostaglandin (e.g., PGE2) synthesis. The role of prostaglandins, and PGE2 in particular, in the generation of pain was demonstrated decades ago (Ferreira et al., 1978). In humans, tissue levels of PGE2 are increased during acute inflammation (e.g., third molar extraction), and the reduction in these levels by NSAIDs is associated with their analgesic efficacy (O’Brien et al., 1996; Roszkowski et al., 1997). However, the mechanisms mediating prostaglandin regulation of trigeminal nociceptor activity remain unknown.
Molecular cloning studies have identified several EP receptor subtypes that might mediate this effect (Coleman et al., 1994). The receptor EP1 signals via the Gq-phospholipase C pathway, whereas the EP2, EP3C, and EP4 subtypes signal predominantly via the Gs-cyclic AMP pathway (Boie et al., 1997; Southall and Vasko, 2001). Activation of these pathways might contribute to previous observations conducted with somatic dorsal root ganglia neurons, where PGE2 was shown to sensitize the transient receptor potential subtype V1 (TRPV1) receptor, a well-recognized receptor contributing to inflammatory hyperalgesia (Lopshire and Nicol, 1998; Caterina et al., 2000; Southall and Vasko, 2001; Moriyama et al., 2005). Despite several similarities, important differences exist between trigeminal and dorsal root ganglia systems. They include the lack of sympathetic sprouting upon nerve injury in the trigeminal system (Bongenhielm et al., 1999), and differences in the development and co-expression patterns of various proteins (Ichikawa and Sugimoto, 2002; Price and Flores, 2007). These differences necessitate a separate investigation into the identification of EP receptors mediating orofacial pain. Although functional studies in the trigeminal system have implicated the co-expression of PGE2 receptors and TRPV1 (Goodis et al., 2000; Price et al., 2004), no study to date has identified the EP receptor subtypes expressed with TRPV1 in the trigeminal sensory neurons. Moreover, the effects of the EP receptor-selective agonists on TRPV1 responses are not known.
In the present study, we hypothesized that certain EP receptor subtypes are co-expressed with TRPV1 in trigeminal neurons, and that their activation leads to sensitization of TRPV1 responses in these neurons.
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MATERIALS & METHODS
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Animals
Adult male Sprague-Dawley (Charles River, Wilmington, MA, USA) rats weighing 250–300 g were used in this study. All animal study protocols were approved by the Institutional Animal Care and Use Committee of the University of Texas Health Science Center at San Antonio and conformed to the International Association for the Study of Pain (IASP) and Federal guidelines. Animals were housed for 1 wk prior to the experiment, with food and water available ad lib. The total number of animals used for this study was 27 (6 for the ISH-IHC studies and 21 for the culture studies).
Compounds
Prostaglandin E2 (PGE2) (Cayman Chem., Ann Arbor, MI, USA) and capsaicin (Sigma-Aldrich, St. Louis, MO, USA) were prepared in stock solutions with ethanol and diluted by buffer on the day of the experiment (final < 0.01% EtOH). Sulprostone and Butaprost (Cayman Chem.) were commercially available in methyl acetate and were further diluted in experimental buffer (final < 0.1% methyl acetate). All control experiments contained appropriate vehicles that were without effect in these assays.
Rat Trigeminal Ganglia (TG) Primary Culture
Cultures were generated as described previously (Patwardhan et al., 2005). For details, see the APPENDIX.
CGRP Release Assay
All culture experiments were performed on day 5–6, at 37°C, with modified Hanks’ buffer (Gibco, Carlsbad, CA, USA) that also contained 10.9 mM HEPES, 4.2 mM sodium bicarbonate, 10 mM dextrose, and 0.1% bovine serum albumin. After 2 initial washes, a 15-minute baseline sample was collected. The cells were then exposed to either PGE2 (1 µM), sulprostone (1–10 µM), butaprost (1–10 µM), or vehicle for 15 min, after which supernatant was collected. For experiments evaluating the effect of EP agonist pre-treatment on capsaicin-evoked release, we first collected supernatant, to determine whether the agonist altered basal release, and then collected fresh supernatant after the application of capsaicin (30 nM, 15 min). The released iCGRP was measured by radioimmunoassay (RIA) with a previously validated (Traub et al., 1989) CGRP antibody (for the details of RIA, please refer to the APPENDIX). The basal release was typically 6–8 fmol per well. All experiments were repeated at least 3 times.
Riboprobe Synthesis, in situ Hybridization (ISH), and Immunohistochemistry (IHC)
Full-length riboprobes containing digoxigenin-UTP against EP receptor subtypes (accession #s: EP1, NM_013100; EP2, NM_031088; EP3, X83855; EP4, NM_032076) were synthesized. The riboprobe against EP3 had more than 85% homology with all the EP3 subtypes (i.e., EP3A-C, etc.). Fixed, frozen sections were used for the anatomical studies (for details of tissue preparation and hybridization, see the APPENDIX). In situ hybridizations (58°C) were carried out as described previously (Zaidi et al., 2000), with DIG-cRNA-labeled probes, and the hybridization was detected with TSA-Plus Cyanine 3 (PerkinElmer LAS, Boston, MA, USA), according to the manufacturer’s instructions. Slides were then incubated with a previously characterized (Guo et al., 1999) guinea pig anti-TRPV1 antibody (1:3000, cat# GP14100, Neuromics, Bloomington, MN , USA) overnight at 4°C and detected with an Alexa-488-conjugated fluorescent secondary antibody (1:300, Molecular Probes, Eugene, OR, USA). Sense riboprobes served as a negative control.
Image Acquisition and Cell Counting
Images were acquired with the use of a Nikon Eclipse 90i microscope (Melville, NY, USA) equipped with a Nikon Digital Sight DS-2Mv CCD camera at 10x. We used Nikon NIS-Elements F v2.10 (Build 217) image EZ-3.20 acquisition software to acquire the images. We used NIH ImageJ software to perform quantitative analysis, as described previously (Alvarado et al., 2007). For details of the cell selection criteria, see the APPENDIX.
Data Analysis
We analyzed the data using GraphPad Prism software, version 4 (GraphPad Software Inc., San Diego, CA, USA). The CGRP data are presented as percent of basal release (mean ± SEM). The statistical analysis was performed by one-way ANOVA to assess whether the treatment (drug at various concentrations) was significantly different from the vehicle. If ANOVA demonstrated a significant difference, differences between individual groups were analyzed with the Bonferroni post hoc test. The cell-counting data were presented as cells expressing one parameter as a percentage of a second parameter.
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RESULTS
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We first synthesized full-length riboprobes against the mRNA sequences encoding the EP receptor subtypes 1–4. Hybridization with these 4 probes demonstrated that EP1 and EP4 mRNA was found in less than 5% of all trigeminal neurons (data not shown), and thus we concentrated on the EP2 and EP3 expression patterns for further quantification. Representative images of EP2 mRNA co-expression with TRPV1 protein are presented in Fig. 1A . EP2 mRNA was detected in approximately 58% of total neurons (958/1682 neurons, Fig. 1B). In the same sections, TRPV1 protein was found in approximately 39% of total neurons (659/1682 neurons). Although this proportion is slightly higher than that reported by others (Biggs et al., 2007), it is very similar to results obtained during the initial characterization of this antibody, as well as to previous findings from our lab (Guo et al., 1999; Dussor et al., 2003). Further analysis of the co-expression patterns of these 2 receptors revealed that ~ 64% of TRPV1-expressing neurons co-expressed EP2 (426/659 neurons). Conversely, approximately 44% of EP2-expressing neurons co-expressed TRPV1 (426/958 neurons). The cell size distribution analysis showed that most of the cells (77%) that expressed EP2 mRNA had diameters of less than 30 µm (Fig. 1C). This distribution profile suggests a significant expression in the C and A fiber populations.
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Figure 1. Co-expression of EP2 with TRPV1 in trigeminal sensory neurons. (A) Freshly isolated rat trigeminal ganglia were fixed, frozen immediately, and sectioned. The ISH-IHC was performed with a riboprobe against EP2 and an antibody against TRPV1 protein, respectively. A representative image demonstrating the co-expression of EP2 mRNA and TRPV1 protein is shown. The horizontal arrows denote examples of cells that expressed both. The vertical arrows in the image under the EP2-mRNA heading denote examples of cells that expressed only EP2, but not TRPV1. Conversely, the vertical arrows in the image under the TRPV1-protein heading denote examples of cells that expressed only TRPV1, but not EP2. A scale bar (50 µm) is shown at the bottom left of the image. (B) Cell counting was performed on trigeminal ganglia from multiple rats (N = 3, mean ± SEM), and data are represented as percent of cells expressing the given criteria. The total numbers of neurons counted for particular criteria are shown on individual bars. (C) Cell size distribution of cells counted across all the animals was measured and presented as percent of total cells in the respective diameter range.
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Since the next most abundant EP receptor mRNA was EP3, we performed similar analyses on EP3 expression patterns in rat trigeminal neurons. The EP3 riboprobe has high homology with all the EP3 subtypes, and hybridization results were therefore interpreted to indicate overall expression of the EP3 subtype. A representative image of EP3 mRNA co-expression with TRPV1 protein is demonstrated in Fig. 2A. EP3 message was found in approximately 53% of total trigeminal neurons (908/1713 neurons, Fig. 2B). TRPV1 protein was observed in ~ 37% of total trigeminal neurons (623/1713 neurons). The co-expression pattern analysis showed that ~ 67% of TRPV1 (421/623 neurons)-expressing neurons demonstrated EP3 message, whereas ~ 48% of EP3 (421/908 neurons)-expressing neurons demonstrated TRPV1 protein. Similar to that observed with EP2, a majority (78%) of EP3-expressing cells had smaller diameters (< 30 µm, Fig. 1C ).
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Figure 2. Co-expression of EP3 with TRPV1 in trigeminal sensory neurons. (A) Freshly isolated rat trigeminal ganglia were fixed, frozen immediately, and sectioned. The ISH-IHC was performed with a riboprobe against EP2 and an antibody against TRPV1 protein, respectively. A representative image demonstrating the co-expression of EP3 mRNA and TRPV1 protein is shown. The horizontal arrows denote examples of cells that expressed both. The vertical arrows in the image under the EP3-mRNA heading denote examples of cells that expressed only EP3, but not TRPV1. Conversely, the vertical arrows in the image under the TRPV1-protein heading denote examples of cells that expressed only TRPV1, but not EP3. A scale bar (50µm) is shown at the bottom left of the image. (B) Cell counting was performed on trigeminal ganglia from multiple rats (N = 3, mean ± SEM), and data are represented as percent of cells expressing the given criteria. The total numbers of neurons counted for particular criteria are shown on individual bars. (C) Cell size distribution of cells counted across all the animals was measured and presented as percent of total cells in the respective diameter range.
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Since substantial co-expression of certain EP receptor subtypes (i.e., EP2 and EP3) was observed with TRPV1 protein, we next evaluated whether application of EP subtype-selective agonists (butaprost and sulprostone) had any effect on iCGRP release from cultured trigeminal neurons, and whether these agonists sensitized TRPV1 responses. The vehicle treatment did not affect either the basal or the capsaicin-evoked release of iCGRP. Pre-treatment with the EP2 agonist, butaprost, evoked iCGRP release that was statistically significant at 10 µM (65% above basal, p < 0.001), with a trend toward increased release observed at 1 µM. Similar results were obtained with sulprostone (EP3 agonist), where the evoked release at 10 µM concentration was significant (678% above basal, p < 0.001, Fig. 3A). The evoked release by sulprostone was more robust than that evoked by butaprost. Next, we evaluated the effect of pre-treatment with these agonists on capsaicin-evoked iCGRP release (Fig. 3B). The pre-treatment with PGE2 (1 µM) or butaprost (10 µM) for 15 min significantly (p < 0.05 and p < 0.01, respectively) enhanced capsaicin-evoked iCGRP release (40%). Since sulprostone alone evoked iCGRP release similar to what we observed with capsaicin (30 nM), it was difficult to interpret its sensitization effect in this assay. The major concern was the possibility of peptide depletion upon successive applications of sulprostone and capsaicin. Application of a lower concentration (1 µM) of sulprostone did not evoke a significant amount of iCGRP release on its own, nor did it enhance capsaicin-evoked response. Similarly, a lower concentration of butaprost (1 µM) did not sensitize capsaicin-evoked response.
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Figure 3. Effects of EP2 and EP3 agonists in trigeminal sensory neurons. (A) Cultured trigeminal ganglia neurons were exposed to either vehicle or butaprost (1 µM and 10 µM, 15 min) or sulprostone (1 µM and 10 µM, 15 min), and the supernatant was collected for measurement of the amount of iCGRP by radioimmunoassay [n = 6–18 wells per condition; data presented as % of basal release (mean ± SEM); *** = p < 0.001; butaprost- and sulprostone-evoked release was compared with the vehicle treatment by one-way ANOVA with the Bonferroni post hoc test]. (B) Cultured trigeminal ganglia neurons were exposed to either vehicle, butaprost (10 µM), or PGE2 (1 µM) for 15 min, and the supernatant was removed. The neurons were then exposed to capsaicin (30 nM, 15 min), and the supernatant was measured for amount of iCGRP [n = 6 wells per condition; data presented as % of basal release (mean ± SEM); *p < 0.05, **p < 0.01; capsaicin-evoked release following either PGE2 or butaprost pre-treatment was compared with vehicle pre-treatment by one-way ANOVA with the Bonferroni post hoc test].
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DISCUSSION
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The results presented in this study demonstrate that the PGE2 receptors, EP2 and EP3, are co-expressed with the nociceptive marker TRPV1 in trigeminal sensory neurons. Moreover, EP2 and EP3 agonists modulate trigeminal neuronal activity.
Several anatomical studies have characterized EP receptor expression in dorsal root ganglia sensory neurons (Sugimoto et al., 1994; Oida et al., 1995). They have demonstrated the presence of all 4 EP receptor subtypes in dorsal root ganglia neurons. Similarly, both in vitro and in vivo functional studies have demonstrated the role of at least one of these subtypes in mediating PGE2-evoked hyperalgesia or sensitization of nociceptive responses (Jenkins et al., 2001; Southall and Vasko, 2001; Moriyama et al., 2005). However, detailed anatomical studies in the trigeminal system, especially in relation to the capsaicin-sensitive subset of nociceptors (TRPV1-positive), have not been reported.
Our studies implicate EP2 and EP3 as possibly mediating most of the effects of PGE2 in modulating native trigeminal nociceptors. These findings extend those of previous studies attempting to characterize functional EP receptor subtypes in trigeminal neurons (Jenkins et al., 2001), and document a functional interaction between PGE2 receptors and the capsaicin receptor in the trigeminal system (Price et al., 2004). Our results are in agreement with those from other studies that have shown the functional role of EP2 and EP3 in the dorsal root ganglia system (Southall and Vasko, 2001; Chang et al., 2005). However, studies performed in cultured dorsal root ganglia neurons and in the spinal pain system have also implicated EP1 and EP4 in PGE2 modulation of these nociceptors (Southall and Vasko, 2001; Moriyama et al., 2005; Lin et al., 2006). One of the reasons for this discrepancy may be that trigeminal and dorsal root ganglia have different expression patterns for these receptors. Alternatively, inflammation or culturing conditions may differentially alter the expression of EP1 and EP4 in trigeminal vs. dorsal root ganglia neurons.
In the studies performed in cultured trigeminal neurons, we used an EP2-specific agonist, butaprost, and an EP3 agonist, sulprostone. Marked differences were observed in the efficacy of these agonists in evoking iCGRP release. The magnitude of both butaprost-evoked release and sensitization of TRPV1 response was very similar to that of PGE2. Although PGE2 activates all EP receptors with near-equal affinity, some of the EP receptor subtypes are also known to couple to inhibitory G-proteins (Sugimoto and Narumiya, 2007). Thus, the overall response generated by PGE2 might represent a summation of its action on both excitatory and inhibitory receptors. Interestingly, sulprostone-evoked release was substantially higher than that of either butaprost or PGE2 alone. Several possibilities might contribute to this finding. First, although both EP2 and EP3 signal via the Gs-cAMP-PKA pathway (Boie et al., 1997), EP3 is also known to signal via other pathways, such as G12/13 and PKC (Katoh et al., 1996; Claudino et al., 2006; Wise, 2006), which may have greater efficacy in triggering exocytosis. Second, sulprostone also activates other EP receptors (Boie et al., 1997), and it is possible that the sulprostone effect may demonstrate a positive interaction among multiple signaling pathways. Indeed, in dorsal root ganglia neurons, simultaneous activation of the PKA and the PKC pathways results in a synergistic effect on neuropeptide release (Vasko et al., 1994). Importantly, activation of both of these pathways is known to sensitize TRPV1 responses (Lopshire and Nicol, 1998; Premkumar and Ahern, 2000). Thus, EP2 and EP3 agonists possibly sensitize TRPV1 responses via one of these pathways. Further studies with specific blockers of PKA and PKC would elucidate the relative contributions of these pathways in the observed effect.
The activation of both PGE2 receptors and TRPV1 has been implicated in the generation of orofacial pain (Kopp, 2001; Sato et al., 2005), and analysis of the present data supports the hypothesis that prostaglandins regulate trigeminal TRPV1 nociceptors via activation of the EP2 and EP3 receptors. In light of the side-effects of NSAID therapy (Simon and Mills, 1980), specific antagonists for EP2 and EP3 might be useful in the treatment of inflammatory orofacial pain.
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ACKNOWLEDGMENTS
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This research was supported by P01 DA016179 (KMH), R01 DA19585 (KMH), F30 DE017307-01 (JV), Co*STAR T-32 DE14318 (KC), and ASPET SURF grant (JF). We thank Dr. Jill Fehrenbacher for helpful discussions regarding selection of EP agonists, and Dr. Michael Henry for suggestions on the in situ protocol. We also acknowledge the technical help provided by Griffin Perry and Gabriela Helesic.
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FOOTNOTES
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A supplemental appendix to this article is published electronically only at http://jdr.iadrjournals.org/cgi/content/full/87/3/262/DC1.
Received for publication August 17, 2006.
Revision received October 23, 2007.
Accepted for publication December 11, 2007.
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Journal of Dental Research, Vol. 87, No. 3,
262-266 (2008)
DOI: 10.1177/154405910808700306
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ABSTRACT
INTRODUCTION