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Anesth Analg 2006;102:443-447
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000194587.94260.1d

ANESTHETIC PHARMACOLOGY

The Additive Antinociceptive Interaction Between WIN 55,212-2, a Cannabinoid Agonist, and Ketorolac

Ahmet Ulugöl*, Filiz Özyigit*, Özgür Yesilyurt{dagger}, and Ahmet Dogrul{dagger}

*Department of Pharmacology, Trakya University, Edirne, Turkey, and {dagger}Gülhane Academy of Medicine, Ankara, Turkey

Address correspondence and reprint requests to Ahmet Dogrul, MD, Gülhane Military Medical Academy, Faculty of Medicine, Department of Medical Pharmacology, Ankara, Turkey. Address e-mail to dogrula{at}gata.edu.tr


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Combinations of nonsteroidal antiinflammatory drugs (NSAIDs) and opioids are widespread in the management of pain, allowing better analgesia with reduced side effects. Cannabinoids are promising analgesic drugs that have pharmacological properties similar to those of opioids. However, the beneficial effects of cannabinoids for pain treatment are counterbalanced by their psychotomimetic side effects. We designed the present study to evaluate the antinociceptive interaction between cannabinoids and NSAIDs in mice, using the acetic acid-induced writhing test and tail-flick test. Interactions were analyzed using isobolographic analysis. WIN 55,212-2, a cannabinoid agonist, and the NSAID ketorolac, either alone or in combination, produced dose-dependent antinociception in the writhing test. Isobolographic analysis showed additive interactions between WIN 55,212-2 and ketorolac when they were coadministered systemically. Ketorolac is inactive in the radiant heat tail-flick test in which WIN 55,212-2 was active. Ketorolac did not influence WIN 55,212-2–induced antinociception in the tail-flick test. This study demonstrated an additive antinociceptive interaction between WIN 55,212-2 and ketorolac in an inflammatory visceral pain model. The combination of cannabinoids and NSAIDs may have utility in the pharmacotherapy of pain.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Combinations of analgesic drugs from different pharmacological classes are often used for the treatment of clinical pain. The practice of combining opioids with nonsteroidal antiinflammatory drugs (NSAIDs) is widespread in the management of acute and chronic pain (1). The combinations of opioids and NSAIDs are synergistic for analgesia, allowing for a reduction in dosage and a decrease in the incidence of adverse effects compared with using them alone (1,2).

Cannabinoids are analgesic drugs that have similar pharmacological properties similar to those of opioids. They produce analgesia that is comparable with that of opiates in potency and efficacy (3–5). Cannabinoids produce their analgesic activity by activating specific cannabinoid receptors, CB1 and CB2 (6). The expression patterns for cannabinoid receptors support an important role for them in pain processes. The expression of CB1 is restricted to neurons of the central and peripheral nervous systems, including primary afferent neurons (7). In contrast, the expression of CB2 is primarily found peripherally, especially in the cells of the immune system (7).

However, the beneficial effects of cannabinoids in pain treatment are counterbalanced by serious adverse reactions, such as drowsiness, anxiety, and dry mouth, at therapeutic doses (8). It is possible that these undesirable side effects of cannabinoids may be minimized by using combination therapy. Combination analgesic therapy is especially useful when the selected drugs have different mechanisms of action that provide additive or synergistic efficacy, reducing the required doses of the individual drugs compared with monotherapy and potentially limiting side effects. NSAIDs have antinociceptive activity, acting mainly through inhibiting cyclooxygenase enzymes (9). However, there are some studies demonstrating the participation of other systems in the antinociceptive activity of NSAIDs (10). Therefore, additive or synergistic antinociceptive effects are likely to occur after coadministration of cannabinoid and NSAIDs because each group of drugs acts through a different site of action. There are no data on the antinociceptive interaction between cannabinoids and NSAIDs.

The objective of our study was to evaluate a potential antinociceptive interaction between WIN 55,212-2, a mixed CB1/CB2 receptor agonist, and ketorolac, an NSAID, using isobolographic analysis in the radiant heat tail-flick assay, a noninflammatory model of pain, and in the acetic acid writhing test, a model of chemically induced inflammatory visceral nociception (11).


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Adult male Balb-C mice weighing 25–30 g were used. Animals were maintained on a 12-hour light-dark cycle with food and water available ad libitum. This study was conducted according to the guidelines of the Ethics Committee of the International Association for the Study of Pain and was approved by the Animal Care Ethics Committee of Trakya University. Each animal was used only once and received only one dose of the drugs being tested. Eight animals were used for each treatment group.

R-(+)-WIN 55,212-2 was obtained from Sigma-RBI (St. Louis, MO). Ketorolac tromethamine was obtained from Syntex Laboratories Inc (Palo Alto, CA). R-(+)-WIN 55,212-2 was dissolved 50% dimethyl sulfoxide. Ketorolac tromethamine was dissolved in saline. All drugs were freshly prepared and were subcutaneously (s.c.) administered in a volume of 5 mL/kg.

Antinociception was assessed by using the acetic acid writhing test and radiant tail-flick test (9604-A; May-Com, Ankara, Turkey). Writhing responses was elicited by intraperitoneal (i.p.) injection of 0.6% acetic acid in a volume of 10 mL/kg, after which the number of writhes was counted.

The antinociceptive effects produced by WIN 55,212-2 and ketorolac, given either individually or in combination, were studied. WIN 55,212-2 (1, 5, and 10 mg/kg, s.c.) and ketorolac (1, 5, and 10 mg/kg, s.c.) were given to different groups of mice. To perform isobolographic analysis, the fixed combination of WIN 55,212-2 and ketorolac at a ratio of 1:1 was used. Fifty minutes after drug or drug combination administration, acetic acid was injected i.p., and the number of writhes was counted during a 10-min period, starting 10 min after the administration of the acetic acid solution.

In the radiant tail-flick test, baseline tail-flick latency (BL) for each mouse typically ranged from 2 to 3 sec. Cut-off time was set at 7 sec to prevent tissue damage. After baseline responses were established, WIN 55,212-2 (1, 5, and 10 mg/kg, s.c.), ketorolac (1, 5, and 10 mg/kg, s.c.), and combinations were given to different groups of mice. The test latencies of mice were tested at 60 min after administration of drug or drug combination.

In the writhing test, the degree of antinociception was expressed as the percentage decrease in the number of writhes and was calculated according to the formula: % inhibition of writhing = (C – T)/C x 100, where C is the mean number of writhes in saline-treated mice and T is the number of writhes in drug-treated mice. In the radiant tail-flick test, the data were expressed as percentage antinociception, which was calculated using the equation: % Antinoception = [(TL – BL)/(7 – BL)] x 100, where TL is test latency and BL is baseline tail-flick latency. All values were expressed as mean ± sem. Comparisons of the means of two groups were performed with Student's t-test for nonpaired and paired data. Several treatment groups were compared with the control group by using analysis of variance followed by the Dunnett test. The differences between means were considered significant when the value of P was < 0.05. To determine whether the antinociceptive interaction between WIN 55,212-2 and ketorolac was additive or synergistic, isobolographic analysis was performed by the method of Tallarida (12). The construction of the dose-effect curves and determination of doses producing 50% inhibition of writhes (ED50), as well as 95% confidence intervals (CIs), were determined from regression analysis of the linear portion of the dose-response curves using the Visual Basic program FlashCalc (Michael H. Ossipov, personal communication, 2005). The ED50 values and 95% CIs for each drug alone were plotted on the x and y axes, and the ED50 value and CI for the combination were placed in the dose field. The theoretical additive lines represented by the diagonal line connecting the ED50 doses on the x and y axes and the theoretical additive point were calculated according to the method described by Tallarida (12). Drug interactions were considered to be synergistic if the combination ED50 point was below the theoretical additive line. Statistical significance between theoretical additive points and experimental points was evaluated according to Tallarida (12). The method of total fractions was calculated to obtain the magnitude of the interaction. The fractional value describes the experimental ED50 as a fraction of the additive ED50. Values near 1 indicate additive interaction, values <1 indicate a synergistic interaction, and values more than 1 imply an antagonistic interaction.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
After saline injections, the number of writhes was 25.8 ± 2.23 in control animals. Vehicle (50% dimethyl sulfoxide) administration in a volume of 5 mL/kg did not alter acetic acid-induced writhing response (23.75 ± 0.54). WIN 55,212-2 (1, 5, and 10 mg/kg, s.c.) and ketorolac (1, 5, and 10 mg/kg, s.c.) exerted similar dose-dependent antinociceptive activity in the acetic acid-induced writhing test (Fig. 1). The smallest dose (1 mg/kg, s.c.) of WIN 55,212-2 and ketorolac elicited 30% and 33% inhibition, respectively.


Figure 123
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  		Figure 1. Dose–response curves for subcutaneous (s.c.) administration of WIN 55,212-2 and ketorolac for the inhibition of acetic acid writhing response in mice. Each dose point on graph represents mean ± sem from eight animals.

 

The possible antinociceptive interaction between WIN 55,212-2 and ketorolac was tested by combining the two drugs in a fixed dose ratio of 1:1. The inclusion of ketorolac significantly enhanced the antinociceptive activity of WIN 55,212-2 (Fig. 2). Isobolographic analyses demonstrated that the combination of WIN 55,212-2/ketorolac resulted in an additive interaction, because the experimental ED50 value of the WIN 55,212-2/ketorolac combination was not statistically different from the calculated theoretical additive value (Fig. 3). Theoretical and experimental ED50 values with 95% CI for combinations of ketorolac and WIN 55,212-2 administered i.p. in the acetic acid writhing test are shown in Table 1.


Figure 223
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  		Figure 2. Antinociceptive effects obtained with ketorolac and WIN 55,212-2 either alone or in coadministration with ketorolac and WIN 55,212-2 at a fixed dose ratio of 1:1 in acetic acid writhing test. The y axis represents the percentage inhibition of writhing response, the x axis depicts the doses (mg/kg) of ketorolac and WIN 55,212-2 either alone or in combination. Each bar represents mean ± sem from eight animals. Ketorolac enhances the antinociceptive effects of WIN 55,212-2. *P < 0.05, difference from WIN 55,212-2 and ketorolac alone.

 

Figure 323
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  		Figure 3. Isobolograms showing the additive antinociceptive interaction between WIN 55,212-2 and ketorolac after subcutaneous (s.c.) administration in acetic acid writhing test in mice. The experimental points were not significantly different from the calculated additive points, indicating an additive interaction. Each point on the graph represents ED50 values and confidence intervals.

 

View this table:
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  		Table 1. ED50 Values and 95% Confidence Intervals of WIN 55,212-2, Ketorolac, and the Combination of WIN 55,212-2 and Ketorolac Coadministered in a Fixed Dose Ratio of 1:1

 

WIN 55,212-2 (1, 5, and 10 mg/kg) produced dose-dependent antinociception in the tail-flick test (Fig. 4), yielding an ED50 value of 3.95 mg/kg (95% CI, 3.04–5.13). As anticipated, ketorolac in doses of 1, 5, and 10 mg/kg had no observable effect in the tail-flick test. Ketorolac at a fixed dose of 10 mg/kg did not significantly alter the antinociceptive effects of WIN 55,212-2 in the tail-flick test (Fig. 4).


Figure 423
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  		Figure 4. The effect of different doses of WIN 55,212-2, ketorolac alone, and WIN 55, 212 in combination with ketorolac at a fixed dose (10 mg/kg) in the tail-flick test. Each dose point on graph represents mean ± sem from eight animals.

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Combinations of analgesics have been used rationally and successfully in the management of pain. Although cannabinoid compounds have proven analgesic effects, therapeutic use of cannabinoids has been associated with a frequent incidence of side effects. A combination of small-dose cannabinoid (devoid of undesirable side effects) with another group of analgesics could result in analgesia without the adverse effect associated with large-dose cannabinoids. In the present study, the coadministration of a cannabinoid with a NSAID resulted in an additive antinociceptive interaction.

Experimental studies have shown that cannabinoids are highly effective against thermal, mechanical, and chemical pain (5,13–15). Most studies that have investigated the antinociceptive effects of cannabinoids have centered on the use of models that examine reflex responses to a single noxious stimulus, such as the tail-flick or hotplate test (6,16,17). In this study, we used two nociceptive models, the acetic acid writhing test as an inflammatory pain model and the tail-flick test, a reflex response to a single noxious thermal stimulus, as a noninflammatory model for acute nociception (11). In the inflammatory pain model, acetic acid causes tissue damage and releases pain-producing substances, including prostaglandins, that activate peripheral nociceptors on the terminals on the sensory nerve fibers (11,18). Painful stimuli caused by acetic acid reach higher centers by a number of spinal nerve pathways (18). In contrast, the tail-flick test involves nociceptive processing at mainly the spinal and supraspinal levels (11).

In the present study, WIN 55,212-2 and ketorolac alone exhibited comparable dose dependent antinociceptive activity in the writhing test. Our results are consistent with previous reports in which NSAIDs, such as ketorolac, have proven effective for altering acute visceral pain (19). WIN 55,212-2–induced antinociception in the writhing test are also consistent with the ability of cannabinoids to reduce inflammation-induced nociception caused by a variety of inflammatory drugs, such as carrageenan and formalin (14,20). The analgesic action of NSAIDs has been explained by their inhibition of cyclooxygenase, which synthesizes prostaglandins at the peripheral cell-damage sites (9). It is possible that prostanoids released from cyclooxygenase are involved in the processing of acetic acid-induced visceral nociception. Thus, inhibition of cyclooxygenase by ketorolac in peripheral tissue produce antinociception in the writhing test. The antinociceptive activity of cannabinoids is generally believed to be centrally mediated (6). However, several studies showed the importance of the peripheral cannabinoid system in the modulation of pain (3–5). WIN 55,212-2 is a lipophilic substance; thus, after systemic administration, it can act at a number of peripheral, spinal, and supraspinal sites to raise nociceptive thresholds (3). Thus, cannabinoid-induced chemical antinociception can occur at peripheral, spinal and supraspinal sites. It has been reported that the activation of cannabinoid receptors appears to be involved in down regulation of the inflammatory response (21). Thus, the peripheral and/or central component of cannabinoid system activation by WIN 55,212-2 could contribute to its antinociceptive effects in the writhing test.

We analyzed the effects of the combination of cannabinoid and NSAID in the inflammatory pain model. The results obtained in this study showed additive antinociceptive interaction. Thus, administration of a combination of drugs, such as cannabinoids with NSAIDs, can lead to the use of smaller doses of cannabinoids with increased analgesic effect. However, the mechanism of additive interaction between cannabinoid and NSAIDs is unclear. The additivity observed between NSAIDs and cannabinoid may be related to a pharmacokinetic or pharmacodynamic interaction; the latter seems more probable. NSAIDs act mainly through peripheral inhibition of the cyclooxygenase enzyme (9), but a central action has also been described (10). Cannabinoids mainly have a central site of action through interaction with cannabinoid receptors, but a peripheral action also has been shown especially after inflammation (20–22). Therefore, the additive interaction between NSAIDs and cannabinoid may occur at peripheral and/or the central level. Inhibition of the central nervous system cyclooxygenase is probably responsible for most of the central effects of NSAIDs, but it has been reported that NSAIDs activate descending inhibitory antinociceptive pathways (10). It has also been reported that systemic cannabinoids produce antinociception, in part by modulating descending systems to the spinal cord (14). Thus, a central interaction of ketorolac with cannabinoids is possible.

Using the mouse radiant heat tail-flick nociception model, consistent with previous studies, we observed potent antinociceptive effects with WIN 55,212-2 (3,4,15,17). In contrast, in a previous study (23), ketorolac was inactive in this model of moderate to severe pain, reflecting the ceiling effects of NSAIDs. The antinociceptive potency of NSAIDs is known to be dependent on the algesiometric test used. NSAIDs are sensitive to chemical pain models and they are typically not sufficiently effective to demonstrate activity in many of the more rigorous preclinical analgesic assays, such as the radiant heat tail-flick assay (23,24). Unlike the observed additive interactions between WIN 55,212-2 and ketorolac in the inflammatory pain model, in which the NSAIDs would be expected to be active (18,25), ketorolac failed to show any interactions with WIN 55,212-2 in the thermal tail-flick assay. These differences may be due to the type of pain being assessed in different test methods. It is also noteworthy that we were not able to obtain an ED50 value for ketorolac in the tail-flick assay because of its lack of activity in this model.

An additive interaction may be insufficient for the beneficial outcome of an analgesic drug combination, especially if the interactions for adverse effects are not known. In our study, we were unable to evaluate the benefits of a combination of WIN 55,212-2 and ketorolac in terms of side effects. This is important because the combination may accompany a more frequent incidence of side effects than that produced by each alone, reflecting an additive antinociceptive interaction between WIN 55,212-2 and ketorolac. Further study will be required to determine the side effect interaction between cannabinoids and NSAIDs.

In conclusion, isobolographic analysis indicated an additive antinociceptive interaction between cannabinoid and NSAIDs when administered systemically in an inflammatory visceral pain model. The combination of cannabinoids with NSAIDs may have utility in pain pharmacotherapy.


   Footnotes
 
Accepted for publication September 19, 2005.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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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