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Anesth Analg 2004;99:1166-1172
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000130348.85587.BE

PAIN MEDICINE

Michael J. Cousins Section Editor

Bradykinin Antagonists Have No Analgesic Effect on Incisional Pain

Paul A. Leonard, MD PhD, Radha Arunkumar, MD, and Timothy J. Brennan, MD PhD

Department of Anesthesia, University of Iowa, Iowa City, Iowa

Address correspondence and reprint requests to Timothy J. Brennan, MD, PhD, Department of Anesthesia, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA 52246. Address e-mail to timothy-brennan{at}uiowa.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Bradykinin, an endogenous nonapeptide and an important mediator of inflammation, is also implicated in the initiation and maintenance of pain. Both des-Arg8, Leu8-bradykinin (dALBK) and HOE-140, the prototypic bradykinin B1 and B2 receptor antagonists, respectively, have been shown to reduce pain behaviors and inflammation in animal models of persistent nociception. We studied them for activity against incision-induced pain behaviors in a rat model for postoperative pain. A 1-cm plantar incision was made in the hind paw of halothane-anesthetized rats and closed with 5–0 nylon. Withdrawal responses to punctate and nonpunctate mechanical stimuli were tested with von Frey filaments and a plastic disk attached to a von Frey filament, respectively. Withdrawal latency to radiant heat was also tested. Rats were tested 1 day before the incision, 1 h after the incision, and 0.5, 1, 1.5, and 2.5 h after the injection of the drug. They were then retested at the same times before and after the injection of the drug on each of the first 2 postoperative days. The rats received the saline vehicle dALBK (0.1, 0.3, 1.0, or 3.0 mg/kg) or HOE-140 (0.1, 0.3, 1.0, or 3.0 mg/kg) IV. Another group of rats had the drug injected 1 h before incision and tested as above. Statistical significance (P < 0.05) was determined with Kruskal-Wallis test and a two-way analysis of variance. None of the doses of either dALBK or HOE-140 affected the responses to punctate or blunt mechanical stimulation or heat, either as a pretreatment or as a posttreatment. These data support the unique mechanisms for incision-induced pain relative to inflammation-related pain. Although inflammation may represent a component of incisional pain, the etiology of inflammation and its role seem different than in other models.

IMPLICATIONS: Bradykinin antagonists reduce pain behaviors and inflammation in animal models of persistent nociception. We studied the effects of bradykinin antagonists in a rat model of postoperative pain.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Given that postoperative pain continues to be a problem in some settings, novel drugs may replace or augment our current tools. The large variety of mediators involved in the development and maintenance of pain suggests that there are many unexplored possibilities for such a novel drug.

Bradykinin, an endogenous nonapeptide and an important mediator of inflammation, is also implicated in the initiation and maintenance of pain. It induces pain by direct activation of nociceptive nerve terminals, by sensitizing other fibers (silent nociceptors) to become nociceptors, and by stimulating the release of other substances such as neurokinin A, substance P, prostanoids, and cytokines involved in nociception (1–3). Two classes of bradykinin receptors have been identified: B1 receptors activated selectively by des-Arg9-bradykinin and des-Arg10-kallidin, the active metabolites of bradykinin and kallidin, and B2 receptors activated selectively by bradykinin and kallidin (4). Evidence for a B3 receptor in the guinea-pig trachea has been reported (5), but no clear conclusion has been made regarding its existence (6).

The prototypic synthetic antagonist for the B1 receptor is des-Arg9, Leu8-bradykinin (dALBK) (7). HOE-140 is a potent B2 receptor selective antagonist, which is stable in solution and has prolonged action in vivo because it is not degraded by bradykinin-metabolizing enzymes (8,9). Both dALBK and HOE-140 reduce pain behaviors and inflammation in animal models of persistent nociception (10–12).

We have previously characterized a rat model for postoperative pain (13,14). A plantar incision in the rat hind paw causes pain behaviors that can be measured using mechanical and thermal stimuli. The time course resembles that of clinically observed postoperative hyperalgesia and is inhibited by parenterally administered morphine (15). In the current experiments, we studied the bradykinin antagonists dALBK and HOE-140 for activity against incision-induced pain behaviors in this model for postoperative pain.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Experiments were performed on 71 adult (weight, 300–350 g) male Sprague-Dawley rats (Harlan, Indianapolis, IN) housed in pairs before surgery. These experiments were reviewed and approved by the Institutional Animal Care and Use Committee at the University of Iowa. The animals were treated in accordance with the Ethical Guidelines for Investigations of Experimental Pain in Conscious Animals, as issued by the International Association for the Study of Pain. Food and water were unrestricted. After surgery, the rats were housed individually in clean bedding of organic cellulose fiber (Shepherd Specialty Papers, Kalamazoo, MI). The incisions were checked daily, and any sign of wound infection or dehiscence excluded the rat from the study. Two rats were excluded because of wound dehiscence. At the end of the protocol, all rats were killed with a mixture of pentobarbital and phenytoin intraperitoneally administered.

Rats were first prepared with IV catheters. Under anesthesia with 1.5%–2% halothane, the anterior paratracheal region was prepared using povidone-iodine solution. The jugular vein was isolated and cannulated with PE-50 tubing that had been stretched by exposing the distal end to heat and filled with a mixture of heparin and saline. The secured catheter was tunneled subcutaneously to the posterior neck region. The skin was closed with 4–0 silk, and the rat recovered for 2–3 days.

The rats were again anesthetized with 1.5%–2% halothane delivered via a nose cone and then given an IM injection of penicillin in the triceps. A 1-cm longitudinal incision was made through the skin and fascia of the plantar aspect of one hind paw starting 0.5 cm from the proximal edge of the heel extending toward the digits (13). The underlying muscle was dissected out, and a single longitudinal incision was made through the muscle. The skin was then closed with two mattress sutures of 5–0 nylon and the wound site covered with antibiotic ointment. After incision, the rats were allowed to recover in their cages.

On the day of the testing, rats were placed individually on an elevated plastic mesh floor with a clear plastic cage top (21 x 27 x 15 cm) and allowed to acclimate.

For the nonpunctate stimulus, a circular plastic disk (5 mm in diameter) attached to a von Frey filament (400 mN) was applied from underneath the cage directly on the incision: a withdrawal response or lifting of the paw off the mesh by the plastic disk without bending the filament was considered a response. Testing was repeated three times with at least 3 min between measurements, and the percentage response to the nonpunctate stimulus was measured.

Five min after completion of nonpunctate testing, withdrawal responses to punctate mechanical stimulation were determined using calibrated von Frey filaments applied from beneath the cage through openings in the mesh to an area adjacent to the wound. The forces were 15, 30, 54, 61, 94, 119, 142, 198, and 522 mN. Each filament was applied once, starting with 15 mN and continuing with filaments of increasing force until a withdrawal response occurred or 522 mN (the cutoff value) was reached.

Withdrawal latencies to heat were assessed by applying a focused radiant heat source in unrestrained rats, as described by Zahn and Brennan (14), at least 10 min after testing for response to punctate stimulus. The heat stimulus was light from a 50-W projector lamp, with an aperture diameter of 6 mm, applied from beneath a heat-tempered glass floor (3 mm thick) on the incision. Paw withdrawal latencies were measured to the nearest 0.1 s. Three trials at least 3 min apart were used to obtain an average paw withdrawal latency.

Rats were tested 1 day before incision, 1 h after incision, and 0.5, 1, 1.5, and 2.5 h after injection of the drug. They were then retested at the same times before and after injection of the drug on each of the first 2 postoperative days. The rats received the saline vehicle dALBK (0.1, 0.3, 1.0, or 3.0 mg/kg) or HOE-140 (0.1, 0.3, 1.0, or 3.0 mg/kg) IV. The data from the day of incision and postoperative Day 2 are shown.

Baseline pain behaviors were measured 1 day before plantar incision. This group of rats had the drug (saline, dALBK 3.0 mg/kg, or HOE-140 3.0 mg/kg IV) injected 1 h before plantar incision, and behavioral testing was continued 2 h after incision. The drug was dosed again 12 h later. On the morning of postoperative Day 1, the drug was re-dosed, and 1 h later, the rats were tested for pain behaviors. No further drug injections were made, and rats were tested once the next day (postoperative Day 2). For all experiments, the person performing the behavioral tests was blinded to the drug injected.

The results are expressed as median or mean ± SD when appropriate. The data were analyzed for differences between saline and bradykinin antagonists. For mechanical stimuli, the data were compared using nonparametric tests. The Kruskal-Wallis test for comparisons between groups was used. Significance versus vehicle after the Kruskal-Wallis test was performed using a two-tailed Dunn test. For withdrawal latencies to heat, a two-way analysis of variance (ANOVA) for repeated measures and subsequent one-way ANOVA between groups was used. Significance versus vehicle after the one-way ANOVA between groups was performed using a Dunn test. Because multiple comparisons were made, this was corrected using the Hochberg method (16). P < 0.05 was considered significant.

dALBK was purchased from Sigma (St Louis, MO), and HOE-140 was a gift from Dr. Klaus Wirth of Hoechst AG (Frankfurt, Germany).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The plantar incision decreased the punctate withdrawal threshold, which was stable through the testing period (Fig. 1A). None of the doses of HOE-140 affected the withdrawal threshold after plantar incision. Similarly, the response to pressure on the wound by a blunt mechanical stimulus increased after incision but was not influenced by HOE-140 (Fig. 1B). As shown previously, plantar incision decreased the withdrawal latency to radiant heat; yet, HOE-140 did not affect the response to heat after incision (Fig. 1C). Two days later, in the same rats, baseline responses to the same mechanical and heat stimuli were measured (Fig. 2A–C). For punctate withdrawal responses, only the data at 1.5 h after the drug administration are shown. HOE-140 did not affect any of the nociceptive responses from 0.5 to 2.5 h after injection on postoperative Day 2. Thus, persistent inflammation caused by the incision did not change the response to HOE-140 2 days later.


Figure 1
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  		Figure 1. Nociceptive responses in rats treated with HOE-140 2 h after incision. (A) Withdrawal responses to punctate mechanical stimuli in rats treated with vehicle or HOE-140 (0.1–3.0 mg/kg). The results are expressed as median (horizontal line) with 1st and 3rd quartiles (boxes) and 10th and 90th percentiles (vertical lines). (B) Response frequency to pressure by blunt mechanical stimulation after incision in rats treated with vehicle or HOE-140 (0.1–3.0 mg/kg). (C) Effect of HOE-140 (0.1–3.0 mg/kg) on withdrawal latency to heat caused by incision. The drug was injected at the time shown by the arrow. Data in B and C represent the mean ± SD.

 

Figure 2
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  		Figure 2. Nociceptive responses in rats treated with HOE-140 2 days after incision. (A) Withdrawal responses to punctate mechanical stimuli in rats 1.5 h after treatment with vehicle or HOE-140 (0.1–3.0 mg/kg). Rats were tested from 0.5 to 2.5 h, but only the data from 1.5 h are shown. (B) Response frequency to pressure by blunt mechanical stimulation after incision in rats treated with vehicle or HOE-140 (0.1–3.0 mg/kg). (C) Effect of HOE-140 (0.1–3.0 mg/kg) on withdrawal latency to heat caused by incision. Graphs are described in Figure 1. The drug was injected at the time shown by the arrow.

 
Administration of dALBK after plantar incision did not affect the withdrawal threshold to punctate mechanical stimulation (Fig. 3A). Similarly, the response to blunt mechanical stimulation (Fig. 3B) and heat were not influenced by dALBK injection (Fig. 3C). Two days later, in the same rats, baseline responses to the same mechanical and heat stimuli were measured (Fig. 4A–C). For punctate withdrawal responses, only the data at 1.5 h after the drug administration are shown. On postoperative Day 2, the nociceptive responses from 0.5 to 2.5 h were not influenced by dALBK. The response to dALBK did not change 2 days after incision.


Figure 3
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  		Figure 3. Nociceptive responses in rats treated with des-Arg9, Leu8-bradykinin (dALBK) 2 h after incision. (A) Withdrawal responses to punctate mechanical stimuli in rats treated with vehicle or dALBK (0.1–3.0 mg/kg). (B) Response frequency to pressure by blunt mechanical stimulation after incision in rats treated with vehicle or dALBK (0.1–3.0 mg/kg). (C) Effect of dALBK (0.1–3.0 mg/kg) on withdrawal latency to heat caused by incision. Graphs are described in Figure 1. The drug was injected at the time shown by the arrow.

 

Figure 4
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  		Figure 4. Nociceptive responses in rats treated with des-Arg9, Leu8-bradykinin (dALBK) 2 days after incision. (A) Withdrawal responses to punctate mechanical stimuli in rats 1.5 h after treatment with vehicle or dALBK (0.1–3.0 mg/kg). (B) Response frequency to pressure by blunt mechanical stimulation after incision in rats treated with vehicle or dALBK (0.1–3.0 mg/kg). (C) Effect of dALBK (0.1–3.0 mg/kg) on withdrawal latency to heat caused by incision. Graphs are described in Figure 1. The drug was injected at the time shown by the arrow.

 
Most studies on the analgesic effects of bradykinin antagonists indicate that B2-receptor stimulation may induce B1 receptors, and B1 receptors are critical for the expression of persistent pain. Although antagonism of bradykinin receptors did not influence pain behaviors after incision, these drugs may affect pain behaviors if treatment was initiated before incision. Pretreatment with the largest doses of HOE-140 (3.0 mg/kg) or dALBK (3.0 mg/kg) did not affect the responses to punctate or blunt mechanical stimulation or heat (Fig. 5A–C).


Figure 5
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  		Figure 5. Effect of treatment with vehicle, des-Arg9, Leu8-bradykinin (dALBK) (3.0 mg/kg) or HOE 140 (3.0 mg/kg) before incision on withdrawal threshold to punctate mechanical stimuli, response frequency to pressure by blunt mechanical stimulation, and withdrawal latency to heat. Graphs are described in Figure 1.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Bradykinin has been described as the most potent endogenous pain-producing substance known (17,18). In addition to being a potent mediator of inflammation, bradykinin has also been shown to cause hyperalgesia by direct activation of nociceptors as well as sensitization of nociceptors through the release of other mediators involved in nociception. In an attempt to explore the possibility of the usefulness of bradykinin antagonists in the setting of acute postoperative pain, this study evaluated the effectiveness of B1- and B2-receptor antagonists in a rat model of postoperative pain. In our study, neither dALBK nor HOE-140 effectively modified incision-induced hyperalgesia. We also did not find the different doses or the timing of the dosing to be factors involved. Previous studies have shown that an orally administered B2 antagonist did not affect mechanical responses after incision (19). The dose-response relations for both B1 and B2 receptor antagonists, role of timing of the administration, and examination of a variety of incision-induced pain behaviors were investigated in this study.

Bradykinin-receptor antagonists were developed for the treatment of acute inflammatory pain. In experimental animals, the exogenous administration of bradykinin induced edema and thermal and mechanical hyperalgesia (20,21). In humans, the subcutaneous administration of bradykinin produced erythema indicative of inflammation and only heat hyperalgesia (22). We expected that bradykinin-receptor antagonists would influence heat hyperalgesia, but it remained possible that mechanical responses could also have been affected.

If bradykinin were important for pain behaviors caused by plantar incision, then the parenteral doses of receptor antagonists used in the present study should have influenced pain behaviors. Evidence for this is as follows: First, parenteral HOE-140 antagonizes the actions of exogenous bradykinin; for example, HOE-140 (0.4 mg/kg) reduced the edema caused by the intraplantar administration of bradykinin (21,23). Similar doses of HOE-140 (1–2 mg/kg) prevented the development and reduced the maintenance of visceral hyperreflexia after bladder irritation in a rat model of cystitis (24). HOE-140 (0.4 mg/kg) completely prevented the development and reduced the maintenance of nociceptive behavior caused by the injection of the inflammogen Porphyromonas gingivalis (25). Zymosan-induced mechanical hyperalgesia was reduced by 0.02 mg/kg of HOE-140 (26). Thus, doses of HOE-140 that were much less than those used in the current study influenced inflammation and pain-related behaviors. From other studies, these drugs produced selective responses based upon model and timing of the administration. HOE-140 was ineffective in reversing hyperalgesia induced by either the Freund adjuvant or ultraviolet radiation in rats (27).

Evidence indicates that in normal tissue, B2 receptors are the predominant receptors for bradykinin. However, B1 receptors become prevalent under inflammatory conditions (21,27), in part, through stimulation of B2 receptors, and antagonism of B1 receptors has been quite effective against pain behaviors in several animal models. For instance, dALBK (1 mg/kg) was effective against visceral hyperreflexia when administered after the development of cystitis (24). dALBK (0.3 mg/kg) exhibited antinociceptive effects in both phases of the formalin test (28) and against the Freund adjuvant-induced inflammation (28). dALBK blocked both the development and reversed hyperalgesia caused by capsaicin in very small doses (29), and zymosan-induced mechanical hyperalgesia was reversed by 0.3 mg/kg of dALBK (26). dALBK was effective in reversing and preventing hyperalgesia in ultraviolet radiation in rats (27). Despite using much larger doses than those in other studies, antagonism of B1 receptors did not affect pain behaviors after incision.

In contrast, dALBK and HOE-140 reversed cytokine-induced mechanical hyperalgesia in the rat, whether coadministered with the cytokines intraarticularly or given IV after the intraarticular administration of the cytokines, interleukin-1B (IL-1B), IL-2, and IL-8 (11,30). HOE-140 has been shown to prevent the bradykinin-induced rat knee joint incapacitation by another group as well (31).

Cyclooxygenase inhibitors, such as indomethacin, reduce the excitatory effect of bradykinin on nociceptors, suggesting that the nociceptive action of bradykinin is mediated indirectly via prostanoid production (2,32–34). Bradykinin-induced knee joint incapacitation that was inhibited by indomethacin or HOE-140 pretreatment was restored by prostaglandin E2 administration (31). In keeping with this, it would be expected that bradykinin antagonists might be useful in postoperative pain, where nonsteroidal antiinflammatory drugs, such as ketorolac, have been effective.

Thus, we would have expected that bradykinin might be an endogenous drug released in incisions that may contribute to a variety of pain behaviors after the injury. Because B2 receptors may be involved in the generation of inflammation and the subsequent B1 receptor expression, an effect of HOE-140 on the development and of dALBK on the maintenance of pain behavior was anticipated. However, these very large doses neither before nor after surgery modified the development or maintenance of the pain behaviors, respectively. These data support the unique mechanisms for incision-induced pain compared with inflammation-related pain. Although inflammation may be a component of incisional pain, the etiology of inflammation and its role seem different than in other models.


   Acknowledgments
 
Supported, in part, by National Institutes of Health (Bethesda, MD) grants GM55831 and GM 067762 to T.J.B.


   References
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 Introduction
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 Results
 Discussion
 References
 

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Accepted for publication April 6, 2004.





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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 2004 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press