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Anesth Analg 2001;93:1012-1017
© 2001 International Anesthesia Research Society

PAIN MEDICINE

A Prostaglandin E2 Receptor Subtype EP1 Receptor Antagonist (ONO-8711) Reduces Hyperalgesia, Allodynia, and C-fos Gene Expression in Rats with Chronic Nerve Constriction

Hiroyasu Kawahara, MD*, Atsuhiro Sakamoto, MD PhD*, Shinhiro Takeda, MD PhD*, Hidetaka Onodera, MD PhD*, Junko Imaki, MD PhD{dagger}, and Ryo Ogawa, MD PhD*

*Department of Anesthesiology, {dagger}Depertment of Anatomy, Nippon Medical School, 1-1-5, Sendagi, Bunkyoku, Tokyo, Japan

Address correspondence and reprint requests to Hiroyasu Kawahara, MD, Department of Anesthesiology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan. Address e-mail to kawahara_hiroyasu/anesth{at}nms.ac.jp


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Chronic constriction injury (CCI) of the sciatic nerve in rats induces persistent mechanical hyperalgesia and allodynia. CCI is widely known as a model of neuropathic pain, and many studies using this model have been reported. Recently, c-fos has been used as a neural marker of pain, and various studies have assessed the relationship between hyperalgesia and c-fos expression in the lumbar spinal cord. In this study, we examined the role of a prostaglandin E2 receptor subtype EP1 receptor antagonist (ONO-8711) in a rat CCI model. EP1 receptor antagonist (EP1-ra) oral administration from day 8 to day 14 significantly reduced hyperalgesia and allodynia in the three pain tests on day 15. EP1-ra treatment from day 8 to 14 also reduced c-fos-positive cells in laminae I-II, III-IV, and V-X compared with saline treatment. A single dose of EP1-ra treatment on day 8 significantly reduced hyperalgesia and allodynia at 1 h and 2 h after administration, but the efficacy was not observed at 24 h. We conclude that EP1-ra treatment may be useful for hyperalgesia and allodynia and that EP1 receptor mechanisms are involved in the maintenance of c-fos gene expression induced by nerve injury.

IMPLICATIONS: We examined whether a prostaglandin E2 receptor subtype EP1 receptor antagonist abrogates neuropathic pain induced by chronic constriction injury model in rats. The EP1 receptor antagonist significantly reduced hyperalgasia, allodynia, and c-fos positive cells. These findings suggested that EP1 receptor antagonists may have a role in treatment of neuropathic pain.


   Introduction
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 Abstract
 Introduction
Methods
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 Discussion
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Chronic constriction injury (CCI) of the sciatic nerve in rats induces persistent mechanical hyperalgesia and allodynia (1). In damaged and inflamed tissues, inflammatory mediators, such as prostaglandins, bradykinin, and serotonin, are released from immune cells. These inflammatory mediators could therefore contribute to the peripheral mechanisms of hyperalgesia induced by nerve injury (2). Prostaglandins are generated by most cells in response to mechanical, thermal, or chemical injury and inflammatory insults. Prostaglandin E2 (PGE2) especially has attained recognition as a mediator of hyperalgesia, even though significant quantities of other prostaglandins are released by injury or inflammation. This focus on PGE2 may have arisen because it was found to be a more potent nociceptive agent than prostaglandin F2{alpha} (PGF2{alpha}), prostaglandin D2 (PGD2), or thromboxane A2 in early studies (3).

PGE2 receptors are classified into four subtypes, EP1, EP2, EP3, and EP4. PGE2 induces c-fos expression in osteoblastic cells through the EP1 receptor (4). Recently, c-fos has been used as a marker for various types of noxious stimulation to nerve, including thermal, mechanical, and chemical stimuli. CCI can induce c-fos gene expression in the spinal cord, which may contribute to the development of hyperalgesia and allodynia.

In this study, we used rats with CCI of the sciatic nerve to test the effects of oral administration of an EP1 receptor antagonist (EP1-ra), ONO-8711 (Ono Pharmaceutical, Osaka, Japan), on nociceptive responses and on c-fos gene expression in the spinal cord. Moreover, we compared it with diclofenac sodium, which is used clinically for the relief of acute pain.


   Methods
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 Methods
Results
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The experimental protocol was approved by the local animal ethics committee. Experiments were performed using adult male Sprague-Dawley rats weighing 200–250 g. The rats were housed in clear plastic cages with sawdust bedding at standard room temperature and with a 12-h light-dark cycle. Food and water were freely available.

Neuropathy of the right hind paw was produced according to the method previously described (1). Under sodium pentobarbital anesthesia (50 mg/kg intraperitoneally [IP]), 4 ligatures of 4–0 catgut chrome were tied loosely around the sciatic nerve at approximately 1-mm intervals, taking care not to interrupt the epineural circulation.

All pain tests were carried out by two independent observers. We used three pain tests (thermal test, paw pressure test, and von Frey hair test). Thermal latency was measured with a stopwatch after exposure of the dorsum of the paw to a radiant heat source (a 50-W halogen reflector bulb). This thermal test is a modification of the Hargreaves test. Experiments to test the effects of EP1-ra were done using a Hargreaves testing apparatus (Ugo Basile, Comerio, Italy). The rats were individually placed on a glass plate and the latency until the first sign of paw licking or jumping to avoid the radiant heat source was taken as an index of the pain threshold. Mechanical thresholds were measured with an analgesimeter (Ugo Basile) in the paw pressure test. This device was used to apply a linearly increasing pressure (16 g/s) via a blunt Perspex cone to the hindpaw until the rat withdrew the paw, at which time the pressure was recorded as the threshold value. The cone was applied between the third and fourth metatarsals. The hind paw withdrawal threshold was determined using von Frey hairs and was expressed in grams using 20 hairs ranging from 0.005 g to 75.858 g. Application of the von Frey hairs was done according to the method described previously (5).

For in situ hybridization, rats were anesthetized with 50 mg/kg of sodium pentobarbital and perfused transcardially with 100 mL of saline followed by 500 mL of ice-cold 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4). The lumbar spinal segments (L4-5) were postfixed overnight in the same fixative containing 20% sucrose and 20-µm thick frozen sections were cut on a cryostat. One section was stained with thionin for reference and the others were mounted onto slides (Dako code No. 3003; Dako, Carpinteria, CA). In situ hybridization was performed as described previously (6). Briefly, the sections were dried, digested with proteinase K (10 µg/mL) for 15 min and acetylated with 0.25% acetic anhydride in 0.1 M triethanolamine. Then the sections were dehydrated in an ascending ethanol series and air-dried. The probe (3 x 106 cpm/mL) was dissolved in a buffer containing 50% formamide, 10% dextran, 1 x Denhart’s solution, 12 mM EDTA (pH 8.0), 10 mM Tris/HCl (pH 8.0), 30 mM NaCl, 0.5 mg/mL yeast tRNA, and 10 mM dithiothreitol (DTT), after which 100 µL of probe solution was applied to each slide. Slides were coverslipped and incubated at 65°C overnight. Then the coverslips were removed and the slides were rinsed in 4 x SSC (1 x SSC is 0.15 M NaCl, 0.015 M Na-Citrate, pH 7.5), digested with RNAase A (20 µL/mL) for 30 min at 37°C, and rinsed sequentially in 2 x SSC, 1 x SSC, 0.5 x SSC, and then rinsed for 30 min in 0.1 x SSC at 60°C before finally being dehydrated again. The sections were exposed to radiographic film for 7 days, and then were dipped in nuclear emulsion (1:1 with water, Kodak NTB2, Kodak, Rochester, NY) and exposed for 3 wk before being developed. Hybridized sections were counterstained with thionin. Radioactive cRNA copies were synthesized using T7 polymerase and full-length rat c-fos cDNA (nucleotide No0.142–1211) inserted into the pBluescript KS(+) plasmid (a gift from Dr. I. Verma) with ({alpha}-35S) UTP as described previously (7). The specific activity of the probe was approximately 3.0 x 106 cpm/µg. As a control for nonspecific labeling, a sense probe generated by T3 polymerase was applied to adjacent sections. We used this method to detect of c-fos-positive cells because in situ hybridization has a higher specificity and sensitivity (8) compared with immunocytochemical labeling.

The ipsilateral c-fos-positive cells were quantified by counting all labeled cells in the laminae using five sections randomly taken from the L4-5 cord segments of each rat. The cells were counted under a microscope as described previously (9). Briefly, the gray matter was divided into three regions, laminae I-II (superficial laminae), laminae III-IV (nucleus proprius), and laminae V-X (the neck of the dorsal horn and the ventral horn). Five spinal cord sections per rat were examined and the number of c-fos-positive cells in each rat was averaged to calculate a mean value for reporting.

At first, all rats were subjected to three pain tests on day 0 (unoperated) and to the same tests on day 7 after surgery. To determine the effect of various doses of the EP1-ra (10, 30, or 100 mg/kg), 30 rats received the drug per os, 10 rats received saline per os, and 10 rats received diclofenac sodium (30 mg/kg) per os once a day for 7 days from day 8. Fifty rats were subjected to the same tests again on day 15. After all tests were finished, 20 rats [10 treated with the EP1-ra (30 mg/kg) and 10 treated with saline] were deeply anesthetized and the lumbar spinal segments were removed. Using 20 rats that received a single dose of EP1-ra (10 or 30 mg/kg) per os on day 8, three tests were done at 1, 2, and 24 h after drug administration for determining the onset and the duration of its single-shot analgesic effect. The observers for the behavioral tests were blinded as to drug treatment.

All data were expressed as the mean ± SD. Statistical evaluation of the thermal latency in the thermal test, the mechanical threshold in the paw pressure test, and the hind paw withdrawal threshold in the von Frey hair test was performed in each group with one-way repeated measures analysis of variance. Statistical comparisons between groups for the thermal test, the paw pressure test, the von Frey hair test, and c-fos gene expression were performed by one-way factorial analysis of variance followed by a multiple comparison test (the Bonferroni test). A P value of <0.05 was considered statistically significant.


   Results
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 Methods
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Discussion
 References
 
The values obtained on day 0 in each test and for each rat were relatively stable and showed no significant variation; these data were used as control values. Results on day 7 (postsurgery) showed the mean withdrawal threshold of the right hind paw was significantly decreased compared with that on the left. Thermal latency was 5.5 ± 1.4 s on the right and 8.8 ± 1.8 s on the left in both groups (Fig. 1). Paw pressure latency was 7.5 ± 1.0 s on the right and 10.8 ± 1.4 s on the left in both groups (Fig. 2), and the von Frey hair threshold was 1.70 ± 0.38 g and 22.76 ± 8.19 g, respectively (Fig. 3).



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  		Figure 1. Thermal hyperalgesia was assessed by the thermal test. Oral administration of the EP1-ra significantly reduced the hind paw withdrawal threshold on day 15. Statistical analysis was performed by the Bonferroni test. *P < 0.05 compared with the Saline group (5.06 ± 1.39 s) (n = 10 in each group).

 


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  		Figure 2. Mechanical hyperalgesia was assessed by the paw pressure test. Oral administration of the EP1-ra significantly reduced the hind paw withdrawal threshold on day 15. Statistical analysis was performed by the Bonferroni test. *P < 0.05 compared with the Saline group (7.35 ± 0.60 s) (n = 10 in each group).

 


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  		Figure 3. Allodynia was assessed by the von Frey hair test. Oral administration of the EP1-ra significantly reduced the hind paw withdrawal threshold on day 15. Statistical analysis was performed by the Bonferroni test. *P < 0.05 compared with the Saline group (2.099 ± 3.256 g) (n = 10 in each group).

 
Administration of the EP1 receptor antagonist to rats resulted in significant attenuation of hyperalgesia. The withdrawal thresholds for mechanical and thermal stimuli on the left were similar irrespective of the treatment or time of assessment. For the right hind paw, thermal latency was 6.9 ± 0.9 s (10 mg/kg per os), 7.7 ± 1.9 s (30 mg/kg per os), and 8.2 ± 1.6 s (100 mg/kg per os) (Fig. 1). In addition, the paw pressure latency was 8.8 ± 0.8 s (10 mg/kg per os), 9.4 ± 1.0 s (30 mg/kg per os), and 9.6 ± 1.1 s (100 mg/kg per os) (Fig. 2). Finally, the von Frey hair threshold was 12.69 ± 6.95 g (10 mg/kg per os), 8.18 ± 2.60 g (30 mg/kg per os), and 10.70 ± 7.59 g (100 mg/kg per os) (Fig. 3). A single dose of the EP1-ra attenuated hyperalgesia 1 h and 2 h after administration; however, those analgesic effects were diminished 24 h after administration (Table 1).


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  		Table 1.  The Reaction Time of Pain Tests for a Single Dose of EP1 Receptor Antagonist
 
Administration of the diclofenac sodium to rats had no effect on the withdrawal thresholds for mechanical and thermal stimuli on day 15. For the right hind paw, thermal latency was 5.9 ± 1.9 s, paw pressure latency was 7.8 ± 0.8 s, and von Frey hair threshold was 1.78 ± 0.58 g.

The number of c-fos-positive cells in the spinal cord was significantly less in rats that received EP1-ra than saline (Fig. 4, 5). The number of c-fos-positive cells on the ipsilateral side was 83 ± 17 (laminae I-II), 55 ± 11 (laminae III-IV), 78 ± 12 (laminae V-X) in the Saline group and 29 ± 10 (laminae I-II), 23 ± 12 (laminae III-IV), 41 ± 7 (laminae V-X) in the EP1-ra group (Fig. 4). EP1-ra inhibited the increase in the number of c-fos-positive cells in all laminae, especially laminae I-II (Fig. 5).



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  		Figure 4. The number of c-fos-positive cells in Saline and EP1-ra rats on day 15. Results are expressed per laminar region (laminae I-II, III-IV, V-X). *P < 0.05 compared with the Saline group (2.099 ± 3.256 g). (n = 10, in each group)

 


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  		Figure 5. Detection of c-fos-positive cells in the spinal cord. A, EP1-ra group; B, Saline group. C and D, schematic illustrations of the same spinal cord level for A and B. Oral administration of the EP1-ra (30 mg/kg) significantly reduced c-fos-positive cells on day 15.

 

   Discussion
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 Abstract
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 Methods
 Results
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References
 
Tissue injury results in the production and release of inflammatory mediators that cause pain and hyperalgesia. It is generally accepted that nociceptor sensitization underlies peripheral hyperalgesia induced by inflammatory mediators, and the ability of these mediators to elicit hyperalgesia and to sensitize nociceptors is well established. However, nonsteroidal antiinflammatory drugs (NSAIDS), the most commonly used peripheral acting analgesics, are thought to produce their effect by inhibiting prostaglandin synthesis and prostaglandins cause mechanical hyperalgesia in animals (10). It remains controversial whether prostaglandins sensitize nociceptors to mechanical stimulation.

Prostaglandins are synthesized from arachidonic acid by cyclooxygenase. They activate various second messenger pathways via an interaction with G protein-coupled receptors. The classification of prostaglandin receptors is derived from both the predicted primary amino acid sequences and operational pharmacology. Specifically, the five major subtypes are discriminated according to the rank order of agonist potency for PGD2 (the DP receptor), PGE2 (the EP receptor), PGF2{alpha} (the FP receptor), prostaglandin I2 (the IP receptor), and thromboxane A2 (the TP receptor), as well as the selectivity of synthetic agonists and antagonists. The diversity of the actions of PGE2 is ascribed to the PGE2 receptor subtypes (EP1, EP2, EP3, and EP4) being coupled to different signal transduction pathways.

A selective EP1 receptor antagonist, ONO-8711 [6-[(2S,3S)-3-4-chloro-2-methylphenylsulfonylaminomethyl)-bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid, was synthesized by Ono Pharmaceutical Co., Ltd. The Ki value of this compound for prostanoid receptors stably expressed in Chinese hamster ovarian cells was 1.7 and 0.6 nM for mouse and human EP1 receptors, respectively, whereas it was 67 nM for the mouse EP3 receptor and 76 nM for the human TP receptor. Its Ki values for other receptors, including the mouse DP, mouse EP2, mouse EP4, mouse FP, and human IP receptors, were all >1000 nM. Analysis of its agonistic and antagonistic actions showed that this compound was a competitive antagonist of the EP1 receptor. It inhibited the PGE2-induced increase of cytosolic Ca2+ with a median inhibitory concentration of 0.21 and 0.05 µM for mouse and human receptors, respectively. The chemical synthesis and biological activities of ONO-8711 will be described in detail elsewhere (11). In this study, we did not observe any side effects of the drug of doses from 10 to 100 mg/kg.

Intrathecal (IT) administration of PGD2 and PGE2 induce hyperalgesia in the hot plate test and intrathecal PGE2 and PGF2{alpha} induce allodynia, a state of discomfort and pain evoked by innocuous tactile stimuli (12). Moreover, Minami et al. (12) reported that PGE2 might cause allodynia via EP1 receptors and hyperalgesia via EP2 and/or EP3 receptors in the mouse spinal cord. Specific blockers are only available for the EP1 receptor. In the present study, one of these agents (ONO-8711) blocked hyperalgesia and allodynia induced by CCI. These results may indicate that the EP1 receptor has a role not only in allodynia but also in hyperalgesia, supporting the concept that prostaglandins (probably PGE2) contribute to neuropathic pain. The findings of Minami et al. (12) were different from ours. One reason may be a difference in the selectivity of the drugs used in each experiment.

In this study, administration of the EP1-ra produced complete relief in the thermal test and produced significant but incomplete relief in the paw pressure test and the von Frey hair test on day 15. Different effects were shown in the three tests. There are several reports showing that the different kinds of abnormal pain sensation seen in CCI rats are differentially sensitive to different drugs (13). However, there is no clear evidence that the different tests estimate differential afferent fibers. Meanwhile, we found no effect on mechanically or thermally evoked hyperalgesia/allodynia with very large dose diclofenac sodium. In general, NSAIDs inhibit cyclooxygenase and decrease the products of prostaglandins, including PGD2 and PGE2. PGE2 in particular has attained wide recognition as a mediator of hyperalgesia. A previous study suggested that PGD2 can block PGE2-evoked allodynia (14). NSAIDs inhibit PGD2, which attenuates allodynia, as well as inhibiting PGE2. This may be one of the reasons why NSAIDs such as diclofenac sodium have only a weak effect on hyperalgesia and allodynia.

CCI of the sciatic nerve results in persistent mechanical hyperalgesia together with increased Fos protein expression in the lumbar spinal cord (15). CCI animals developed unilateral hind paw hyperalgesia that persisted unchanged from day 14 to day 55 after surgery, and c-fos expression ipsilateral to the side of injury was significantly correlated with hyperalgesia latency.

In a previous report, no increase was observed in the number of Fos like-immunoreactivity (Fos-LI) neurons in CCI rats that did not receive any stimulation at 14 days after surgery (16). Kajander et al. (17) also described an immediate increase in the number of Fos-LI neurons in the ipsilateral dorsal horn from days 1 to 10 after injury, and this labeling disappeared by 20 days after injury. Hudspith et al. (15) and Chi et al. (18) reported that Fos-LI neurons could be detected for at least one month after surgery. Chi et al. (18) suggested that there was either a continuing peripheral afferent input or changes in the central activity that contributed to the persistent increase of Fos expression. Our findings in this study support the latter opinion.

Massive injury discharges that occur after nerve section, mainly conducted via unmyelinated C-fibers to the spinal dorsal horn neurons, induce spinal hyperexcitability (19) and may lead to chronic neuropathic pain (20). C-fiber terminals in the spinal cord may release neurotransmitters in response to noxious stimulation, such as excitatory amino acids and neuropeptides (21). In agreement with this, an increase of c-fos gene positive cells was induced in the dorsal horn to the spinal cord (22).

In the present study, oral administration of the EP1-ra from 8 to 14 days after surgery significantly reduced hyperalgesia, allodynia, and the number of c-fos gene positive cells. These results suggest that the EP1-ra suppressed CCI-induced mechanical hyperalgesia and allodynia not only at the peripheral site but also centrally (23), indicating that PGE2 released after surgery may activate both peripheral and spinal EP1 receptors. This may be one of the mechanisms by which PGE2 sensitizes sensory neurons to mechanical stimuli.

The EP1-ra was administered orally in the present study, and such oral drugs may be useful for clinical medicine. Further support for a role of prostaglandins in peripheral hyperalgesia was provided by our demonstration that blocking of prostaglandin receptors could relieve hyperalgesia.


   Acknowledgments
 
We would like to thank Ono Pharmaceutical Co., Ltd. for providing ONO-8711.


   References
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 Introduction
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Accepted for publication May 23, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press