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Anesth Analg 2001;92:233-238
© 2001 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MEDICINE

The Effects of Peripheral Administration of a Novel Selective Antagonist for Prostaglandin E Receptor Subtype EP1, ONO-8711, in a Rat Model of Postoperative Pain

Keiichi Omote, MD, Tomoyuki Kawamata, MD, Yoshito Nakayama, MD, Mikito Kawamata, MD, Koji Hazama, MD, and Akiyoshi Namiki, MD

Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Japan

Address correspondence and reprint requests to Keiichi Omote, MD, Department of Anesthesiology, South-1, West-16, Chuoku, Sapporo 060-8543, Japan. Address e-mail to komote{at}sapmed.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Mechanically evoked pain, also known as incident pain, induced by coughing or deep breathing after surgery leads to potentially devastating consequences. It is generally thought that the prostaglandin receptor- (especially, the receptor for prostaglandin E2, EP receptor) mediated sensitization of sensory nerve fibers is a key contributor to the generation of hyperalgesia. We examined whether a peripherally administered novel selective EP1 antagonist, ONO-8711, would be a potential analgesic for incision-induced mechanical hyperalgesia. We used a rat model of postoperative pain introduced by Brennan et al. (1). Withdrawal thresholds to punctate stimulation and response frequencies to nonpunctate mechanical stimulation were determined by using von Frey filaments applied adjacent to the wound and directly to the incision site of the hind paw, respectively. Mechanical hyperalgesia to punctate and nonpunctate stimuli was observed 2 and 24 h after the incision. ONO-8711 (2, 10, or 50 µg) or saline was administered subcutaneously into the hind paw on the ipsilateral side to the incision. ONO-8711 significantly (P < 0.01) increased the withdrawal thresholds to punctate mechanical stimulation and significantly (P < 0.01) decreased the response frequencies to nonpunctate mechanical stimulation in a dose- and time-dependent manner 2 and 24 h after the incision. We conclude that EP1 receptor-mediated sensitization of sensory nerve fibers may contribute to the generation of mechanical hyperalgesia produced by incisional surgery, and that the EP1 receptor antagonist ONO-8711 may be an option for treatment of postoperative pain, especially incident pain.

Implications: The peripheral administration of an antagonist for EP1 receptor that is a subtype of prostaglandin E receptors can inhibit the mechanical hyperalgesia induced by a surgical incision.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Anumber of postoperative adverse consequences are related directly or indirectly to postoperative pain. The most important of these are pulmonary, circulatory, gastrointestinal, and urinary dysfunctions, and undesirable psychologic and emotional reactions. Pain from a surgical incision occurs at rest, and is exacerbated by mechanical stimulation such as coughing and deep breathing. The mechanical sensitivity of a surgical incision is an important property because mechanically evoked pain during function (incident pain) is difficult to manage. Therefore, the target of postoperative analgesic treatment should be to inhibit evoked pain.

An animal model of postoperative pain was introduced by Brennan et al. (1). The obvious advantage of this model is that it closely mimics the peripheral and central components of the human postoperative pain experience. Mechanical hyperalgesia produced by this model should be useful for studying the effective analgesics for postoperative pain. With this model, the analgesic effectiveness of some intrathecally administered analgesics such as morphine, glutamate receptor antagonists, NK-1 receptor antagonist, and opioid receptor-like 1 receptor agonist have been studied (2–4). The model might be also useful in assessing the ability of peripherally acting substances to alter pain behavior.

In peripheral tissue damage and inflammation after surgery, nonneuronal cells produce a variety of chemical mediators that act on nociceptive neurons. Prostaglandins, especially prostaglandin E2 (PGE2), have important intra- and intercellular roles in nociception (5). Prostaglandins are the products of cyclooxygenase metabolism of arachidonic acid and they activate different second messenger pathways via an interaction with G protein-coupled receptors. The apparent differences in cellular responses to PGE2 and the use of selective agonists and antagonists have led to the subdivision of prostaglandin E receptors (EP receptors) into EP1, EP2, EP3, and EP4 subtypes (6). Recently, a novel selective EP1 receptor subtype antagonist, ONO-8711, 6-[(2S,3S)-3-(4-chloro-2-methylphenylsulfonylaminomethyl)-bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid, has been chemically synthesized (7). ONO-8711 is the most selective antagonist for the EP1 receptor (7).

We investigated the role of peripheral EP1 receptors in mechanical hyperalgesia produced by an incision, and we examined whether the peripheral administration of the novel selective EP1 antagonist ONO-8711 would be effective for controlling experimental postoperative pain (incident pain).


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The protocol for this study was approved by the Sapporo Medical University Animal Care and Use Committee. Experiments were conducted on male Sprague-Dawley rats (weighing 250–300 g; Japan SLC, Hamamatsu, Japan) that were housed individually in a temperature-controlled (21 ± 1°C) room with a 12-h light-dark cycle and given free access to food and water.

The surgery was based on the procedure described by Brennan et al. (1). Under general anesthesia (isoflurane 3% in oxygen delivered via a nose cone), the plantar surface of the right hind paw was disinfected with povidone iodine, and 30,000 international units of penicillin-G (Benzylpenicillin; Sigma Chemical, St Louis, MO) was injected into the triceps muscle. A 1-cm longitudinal incision was made through the skin and fascia of the plantar aspect of the foot starting 0.5 cm from the edge of the heel and extending toward the toes. The plantaris muscle was elevated by using forceps and incised longitudinally. The skin was apposed tightly with three simple sutures of 5–0 nylon on a CV-6 needle. After surgery, the animals were allowed to recover in cages.

Unrestrained rats were individually habituated to a plastic cage (28 x 28 x 32 cm) on an elevated wire mesh floor before the start of the experiment. The evaluation of pain behaviors was based on the procedure described by Brennan et al (1).

Withdrawal responses to punctate mechanical stimulation were determined by using calibrated von Frey filaments (0.0045 – 447 g bending force) applied from underneath the cage through openings (12 x 12 mm) in the wire mesh floor to the area adjacent to the wound and to the same area on the noninjured foot. The test was repeated three times at each time point. A withdrawal response was considered to be complete lifting of the hind paw off the surface of the cage or to be flinching. The least force producing a response was considered the withdrawal threshold.

To measure responses to a nonpunctate mechanical stimulus, a circular plastic disk (5 mm in diameter) attached to a von Fey filament (447 g) was applied from underneath the cage through openings in the wire mesh floor directly to the intended incision site. A response to the nonpunctate stimulus was defined as a withdrawal response or lifting of the foot by touching the plastic disk without bending the filament. This test was repeated three times at each time point; from these three trials, the response frequency was calculated.

The novel selective EP1 antagonist ONO-8711 was supplied by Ono Pharmaceutical Co., Ltd. (Osaka, Japan). This compound was dissolved in physiological saline. Under general anesthesia (isoflurane 1.5% in oxygen), 100 µL of ONO-8711 at the dose of 2, 10, or 50 µg was administered manually into the plantar surface of the hind paw on the ipsilateral side to the incision over 3 min to prevent leakage of the drug solution from the wound site.

Before the surgery, control values of withdrawal threshold to punctate mechanical stimulation by von Frey filaments and withdrawal responses to nonpunctate mechanical stimulation by the plastic disk were measured. After 2 h of recovery time after the incision, baseline values of the threshold and response frequency to the punctate and nonpunctate mechanical stimuli, respectively, were determined. ONO-8711 (2, 10, or 50 µg) or saline was administered subcutaneously on the ipsilateral side to the incision. The withdrawal threshold and the response frequency were measured for up to 120 min. On postoperative day 1 (24 h later), the withdrawal threshold and the response frequency were again determined in the same rats. ONO-8711 or saline was administered subcutaneously, and the withdrawal threshold and the response frequency were measured. This experiment was also performed on nonsurgical rats. In six animals, 50 µg of ONO-8711 was administered subcutaneously on the contralateral side to the incision.

The results are expressed as median for ordinal data or mean ± SD. The data were compared by using the Kruskal-Wallis test followed by Dunn’s test for multiple comparison. P < 0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Withdrawal thresholds to punctate mechanical stimulation were remarkably decreased (2.041 g) at 2 h after the incision. The subcutaneously administered ONO-8711 at the three doses, but not saline, significantly (P < 0.05) increased the threshold in a dose- and time-dependent manner (n = 6 in each group) (Fig. 1, top).



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  		Figure 1. Effects of subcutaneous ONO-8711 (2, 10, and 50 µg) and saline on punctate mechanical hyperalgesia caused by incision 2 h (top) and 24 h (bottom) after the surgery (n = 6 in each group). The results are expressed as medians (horizontal lines) with 1st and 3rd quartiles (boxes) and 10th and 90th percentiles (vertical lines).

 
Twenty-four hours after the incision, the baseline thresholds (3.630 g) were comparable to those on the day of surgery; thus, mechanical hyperalgesia was persistent. No effect from the previous treatment was evident. ONO-8711, but not saline, significantly (P < 0.01) increased the withdrawal threshold in a dose- and time-dependent manner (n = 6 in each group) (Fig. 1, bottom). Peak antihyperalgesic effects were observed 30 min after the administration. The durations of the effect after 50 µg of ONO-8711 were 60 and 120 min 2 and 24 h after incision, respectively. Withdrawal thresholds to punctate stimulation on the contralateral hind paw did not show any changes after ONO-8711 administration at all doses 2 and 24 h after incision (data not shown).

Figure 2 (left) shows the changes in the withdrawal threshold on the ipsilateral side to punctate mechanical stimulation 2 h after surgery when ONO-8711 was injected into the contra- or ipsilateral hind paws; 50 µg of ONO-8711 did not induce any changes in withdrawal threshold on the ipsilateral side when injected on the contralateral side to the incision (n = 6). In normal nonsurgical rats (n = 5), 50 µg of ONO-8711 had no effect on the paw withdrawal threshold (Fig. 2, right).



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  		Figure 2. Left, effects of ONO-8711 50 µg injected on the ipsi- and contralateral sides to incision on withdrawal threshold to punctate mechanical stimulation (n = 6 in each group) 2 h after the surgery. Right, effects of ONO-8711 50 µg on withdrawal threshold to punctate mechanical stimulation in nonsurgical rats (n = 5). The results are expressed as medians (horizontal lines) with 1st and 3rd quartiles (boxes) and 10th and 90th percentiles (vertical lines).

 
Response frequencies to nonpunctate stimulation increased from 0% to 96.3% 2 h after the incision. ONO-8711, but not saline, significantly (P < 0.01) decreased the response frequency in a dose- and time-dependent manner (n = 6 in each group) (Fig. 3, left). Peak effects were observed 30 min after the administration.



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  		Figure 3. Effects of subcutaneous ONO-8711 (2, 10, and 50 µg) and saline on nonpunctate mechanical hyperalgesia caused by incision 2 h (left) and 24 h (right) after the surgery (n = 6 in each group). The results are expressed as mean ± SD.

 
The baseline values of response frequency 24 h later were 87.4% (Fig. 3, right). ONO-8711, but not saline, significantly (P < 0.01) decreased the response frequency in a dose- and time-dependent manner (n = 6 in each group), and the peak effect was observed 30 min after the administration. The durations of the effect after 50 µg of ONO-8711 were 90 and 120 min 2 and 24 h after incision, respectively. Response frequencies to nonpunctate stimulation on the contralateral hind paw did not show any changes after the ONO-8711 administration at all doses 2 and 24 h after the incision (data not shown).

When 50 µg of ONO-8711 was injected into the contralateral side to the incision site, the response frequency did not show any changes on the ipsilateral side (data not shown). In the normal nonsurgical rats (n = 5), 50 µg of ONO-8711 did not show any effects on the response frequency (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We demonstrated that withdrawal thresholds to punctate stimulation decreased and response frequencies to nonpunctate mechanical stimuli increased 2 and 24 h after a surgical incision. Hyperalgesia observed 24 h after the incision was comparable to that on the day of the incision. Subcutaneous injection of the novel selective EP1 antagonist ONO-8711 into the incisional site attenuated the punctate and nonpunctate mechanical hyperalgesia in a dose- and time-dependent manner. These findings suggest that activation of a peripheral EP1 receptor subtype would contribute to the development and maintenance of mechanical hyperalgesia induced by a skin incision.

Many chemical mediators released during inflammatory responses after tissue damage induced by incision can activate or sensitize primary afferent nociceptors, either directly, by interacting with receptors on the primary afferent itself, or indirectly, by causing other cell types to release direct-acting agents (5,8). These mediators are therefore likely to contribute to pain and hyperalgesia in incisional sites. Prostaglandins are among the most important mediators of inflammatory hyperalgesia and are generated from arachidonic acid by cyclooxygenase and lipoxygenase enzyme activity. Interest has been focused on PGE2, the predominant prostaglandin produced in most experimental models of inflammation (9). PGE2 is a potent vasodilator and hyperalgesic agent (10). Its vasoactive effects are enhanced by synergistic actions with other inflammatory mediators such as bradykinin and histamine (11). The hyperalgesia produced by PGE2 to mechanical stimuli and to other inflammatory mediators may explain the mechanism of postoperative pain (12). Because prostaglandins act via a number of receptors coupled with second messengers (6), the EP receptor for PGE2 is probably important for the effect on sensory neurons.

EP2 and EP3 receptors are implicated in the PGE2-induced sensitization of heat and bradykinin responses, respectively, of visceral nociceptors (13). However, antagonists for EP2 and EP3 receptors are not presently available, and selectivity of the agonists for each receptor is not absolute (14). ONO-8711, used in this study, is the most selective EP1 antagonist currently available. The Ki values of this compound in Chinese hamster ovary cell lines were 1.7 and 0.6 nM for mouse and human EP1 receptors, respectively, and 67 nM for mouse EP3 receptor and 76 nM for human TP receptor (7). Its Ki values for the other receptors, including mouse DP, mouse EP2, mouse EP4, mouse FP, and human IP receptors, were >1000 nM (7). Analysis of the agonistic and antagonistic actions of ONO-8711 shows that this compound acts as a competitive antagonist at EP1 receptors and inhibits the PGE2-induced increase in cytosolic Ca2+ concentration, with median inhibitory concentrations of 0.21 and 0.05 µM for the mouse and human receptors, respectively (7). These suggest that the EP1 receptor antagonist suppressed the incision-induced mechanical hyperalgesia at the peripheral site. This indicates that an inflammatory mediator, PGE2, released after incisional surgery activates peripheral EP1 receptors. Activation of EP1 receptors stimulates phospholipase C, which enhances the formation of diacylglycerol and inositol-1,4,5-triphosphate, leading to facilitation of an inward calcium current in sensory neurons (15). This may be one of the mechanisms to account for the ability of PGE2 to sensitize sensory neurons to mechanical stimuli.

It is not known which subtype of the EP receptor contributes to mechanical hyperalgesia of somatic nociceptors after incisional surgery. This study showed that peripherally administered EP1 antagonist ONO-8711 effectively inhibited the punctate and nonpunctate mechanical hyperalgesia induced by an incision. This compound administered in nonsurgical animals did not affect the withdrawal thresholds to punctate stimuli. Thus, this EP1 antagonist produces antihyperalgesic effects against mechanical stimulation but not antinociceptive effects. Furthermore, this study showed that this compound administered on the contralateral side of the hind paw to the incision did not inhibit the mechanical hyperalgesia on the ipsilateral side induced by the incision. This indicates that the antihyperalgesic effect of ONO-8711 is produced at the peripheral site but not through systemic action.

In our results, the medians of withdrawal threshold to punctate mechanical stimuli were 2.041 and 3.630 g 2 and 24 h after the surgery, respectively. Chaplan et al. (16) reported that by using von Frey filament, the tactile stimulus producing a 50% likelihood of withdrawal was determined. They reported that median 50% threshold was 2.4 g (1.81–2.76) in a surgical neuropathy model. Under normal conditions, mechanical punctate stimuli with von Frey filaments encompass to be innocuous (bending force of <9 g) and noxious (bending force of >15 g) (17,18). Therefore, the thresholds after the incision may represent mechanical allodynia. In addition, a positive response to the direct blunt (nonpunctate) mechanical stimulus by touching the plastic disk may also represent mechanical allodynia.

In summary, we demonstrated that peripherally administered EP1 antagonist ONO-8711 effectively inhibited the mechanical hyperalgesia induced by an incision. EP1 receptor-mediated sensitization of sensory nerve fibers may be a contributor to the generation of mechanical hyperalgesia produced by an incisional injury. Consequently, the EP1 receptor antagonist ONO-8711 would be a potential analgesic for postoperative pain, especially for incident pain.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain 1996; 64: 493–501.[Web of Science][Medline]
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  4. Yamamoto T, Sakashita Y. The role of the spinal opioid receptor like1 receptor, the NK-1 receptor, and cyclooxygenase-2 in maintaining postoperative pain in the rat. Anesth Analg 1999; 89: 1203–8.[Abstract/Free Full Text]
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  7. Watanabe K, Kawamori T, Nakatsugi S, et al. Role of the prostaglandin E receptor subtype EP1 in colon carcinogenesis. Cancer Res 1999; 59: 5093–6.[Abstract/Free Full Text]
  8. Levine JD, Fields HL, Basbaum AI. Peptides and the primary afferent nociceptor. J Neurosci 1993; 13: 2273–86.[Abstract]
  9. Higgs GA. The role of eicosanoids in inflammation. Prog Lipid Res 1986; 25: 555–61.[Web of Science][Medline]
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  13. Kumazawa T, Mizumura K, Koda H, Fukusako H. EP receptor subtypes implicated in the PGE2-induced sensitization of polymodal receptors in response to bradykinin and heat. J Neurophysiol 1996; 75: 2361–8.[Abstract/Free Full Text]
  14. Kumazawa T, Mizumura K, Koda H. Different mechanisms (receptor subtype and second messenger actions) implicated in PGE2-induced sensitization of the responses to bradykinin and to heat of polymodal receptors. In: Gebhart GF, Hammond DL, Jensen TS, eds. Proceedings of the 7th World Congress on Pain, Vol 2. Seattle, International Association for the Study of Pain, 1994:265–76.
  15. Nicol GD, Klingberg DK, Vasko MR. Prostaglandin E2 increases calcium conductance and stimulates release of substance P in avian sensory neurons. J Neuroscience 1992; 12: 1917–27.[Abstract]
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Accepted for publication August 23, 2000.




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This Article
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press