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Anesth Analg 2000;90:1152-1156
© 2000 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MEDICINE

Antagonism of Antinociception Produced by Intrathecal Clonidine by Ketorolac in the Rat: The Role of the Opioid System

Gopi A. Tejwani, PhD, and Anil K. Rattan, PhD

Department of Pharmacology, The Ohio State University, College of Medicine and Public Health, Columbus, Ohio

Address correspondence and reprint requests to Gopi A. Tejwani, PhD, The Ohio State University, Department of Pharmacology, College of Medicine and Public Health, 5197 Graves Hall, 333 West 10th Ave., Columbus, OH 43210-1239. Address e-mail to Tejwani.1{at}osu.edu


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The management of severe pain may require "balanced analgesia," involving the use of analgesics with different modes of action. Clonidine, an {alpha}2-adrenoreceptor agonist produces analgesia by itself as well as when given with morphine and local anesthetics. Ketorolac is indicated for the management of moderately severe acute pain and causes analgesia equivalent to morphine. This study was designed to investigate whether the addition of ketorolac promotes antinociception produced by intrathecal administration of clonidine in male Sprague-Dawley rats. Intrathecal injection of clonidine (1–30 µg) induced a dose-dependent increase in antinociception as measured by the tail flick (TF) and hot plate tests. Ketorolac alone (150–600 µg) increased the antinociception by 50%–60% only in the TF test. Ketorolac (10 µg) decreased clonidine (10 µg)-induced antinociception from 69.1% ± 7.8% to 23.5% ± 1.6% (P < 0.05) in the TF test and 35.7% ± 4.7% to 4.5% ± 0.1% (P < 0.05) maximum possible effect in the hot plate test. Ketorolac also antagonized the effect of 30 µg of clonidine. The opioid receptor antagonist naloxone antagonized the antinociceptive effect of clonidine and ketorolac, indicating the involvement of the opioid system in the antinociception produced by clonidine or ketorolac. However, neither clonidine nor ketorolac (10-8 to 10-3 M) inhibited the binding of specific ligands to µ-, {delta}-, and {kappa}-opioid receptors, indicating a lack of direct interaction of clonidine and ketorolac with opioid receptors. These results suggest that intrathecal injection of ketorolac antagonizes the antinociception produced by clonidine.

Implications: Clonidine and ketorolac are two important drugs used to give pain relief to patients. We observed that ketorolac inhibits clonidine-induced analgesia in the rat. We recommend that this drug interaction should be taken into account when both clonidine and ketorolac are used together to alleviate pain in patients.


   Introduction
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Despite numerous advances in pain therapy, the treatment of postoperative pain remains a challenge because of the side effects of various analgesics. A concept of "balanced analgesia" involving the principle of multimodal pain therapy has been advocated (1,2). A combination of analgesics working through different mechanisms may reduce the required dose of analgesics, thus reducing the extent of adverse effects experienced by patients. We reported earlier that small doses of midazolam (3) and local anesthetics (4) given intrathecally enhance the antinociceptive effect of morphine. In addition to morphine, clonidine, an {alpha}2-adrenoreceptor agonist, has found a new and possibly significant role in anesthesia and treatment of pain (5). Clonidine is an effective analgesic; however, it reduces, but does not eliminate, pain after surgery (6). To reduce the hemodynamic depression and hypotension associated with large doses of clonidine, small doses of bupivacaine and morphine have been administered with epidural clonidine to enhance postoperative analgesia (2). Ketorolac, a nonsteroidal antiinflammatory drug (NSAID) is indicated for the management of moderately severe postsurgical pain. Patients undergoing hip or knee arthroplasty receiving ketorolac have reported better analgesia and have used less morphine than those receiving placebo (7). The purpose of this study was to explore whether ketorolac could enhance antinociception produced by intrathecal administration of clonidine in rats.


   Methods
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 Methods
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This study received previous approval from the Ohio State University Institutional Laboratory Animal Care and Use Committee. Male Sprague-Dawley rats were anesthetized with ketamine and xylazine and placed into a stereotaxic apparatus. A polyethylene tube (PE 10) was inserted through a slit in the cisternal membrane approximately 8.5 cm down the spinal subarachnoid space to the rostral aspect of the lumbar enlargement according to the method described earlier (3,4). The catheter was fixed to the skull by craniosplastic cement, and the animals were allowed to recover for at least 1 wk.

Rats were randomized to various treatment groups. Clonidine hydrochloride and ketorolac tromethamine were used for intrathecal administration by using a 10-µL Hamilton syringe (Hamilton Co., Reno, NV). The total volume injected was 20 µL (5 µL saline + 10 µL drug + 5 µL saline) and was kept constant in all experiments. The control animals received only the vehicle. A different group of six rats was used for every dose of each drug injected intrathecally in a volume of 10 µL as indicated below.

1. Clonidine alone (1, 10, 30, or 150 µg).

2. Ketorolac alone (30, 150, 300, or 600 µg).

3. Different doses of clonidine plus ketorolac (1 + 1, 10 + 10, 30 + 30, or 150 + 150 µg).

To determine the involvement of the opioid system in mediating the antinociceptive effect of clonidine and ketorolac in some animals, an intrathecal dose of 100 µg/10 µL naloxone was administered 15 min before the administration of these drugs.

The rats were tested for their nociceptive responses using the tail-flick (TF) and hot-plate (HP) tests as described earlier (3,4).

To determine whether clonidine and ketorolac had any effect on the binding of opioid ligands to spinal cord opioid receptors, spinal cords from normal rats not injected with any drugs were used. The details of the binding assays for µ (DAMGO), {delta} (DSLET), and {kappa} (ethylketocyclazocine) are given in our earlier reports (3,4,8).

TF and HP response latencies were presented as mean ± SEM. Comparisons between predrug and postdrug treatment were performed with a one-way analysis of variance followed by the Newman-Keuls t-test. P values <0.05 were considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The injection of the vehicle (0.9% saline) in the rats produced no significant change in the TF and HP response latency (3.5 ± 0.3 s in TF and 10.1 ± 0.6 s in HP). Intrathecally administered clonidine (1 µg– 150 µg) produced a dose- (Fig. 1A) and time-dependent (Fig. 2) increase in the TF and HP response latency. The peak antinociceptive effect was observed 30 min and 15 min after the administration of the clonidine in TF and HP response latency, respectively (Fig. 2). At smaller doses, the clonidine-induced HP response was short lived compared with TF response latency (Fig. 2). At a larger dose (150 µg), the clonidine-induced antinociception was still apparent 5 h after the administration of the drug (Fig. 2). Intrathecally administered ketorolac (30 µg–600 µg), produced a significant dose- (Fig. 1B) and time-dependent (Fig. 3) antinociception in the TF test. Ketorolac-induced antinociception was increased by a maximum of 50%–60% maximum possible effect (MPE) in the TF response latency (Fig. 3), compared with 100% MPE response produced by clonidine (Fig. 2).



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  		Figure 1. Dose-dependent antinociceptive action of intrathecal clonidine (A) and ketorolac (B) in the tail flick ({square}) and hot plate ({blacksquare}) tests. Antinociceptive effects were measured 15 min after the injections. %MPE = percentage maximum possible effect.

 


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  		Figure 2. Dose- and time-dependent antinociception produced by intrathecal clonidine in the tail flick (A) and hot plate (B) tests. % MPE = percentage maximum possible effect.

 


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  		Figure 3. Dose- and time-dependent antinociception produced by intrathecal ketorolac in the tail flick (A) and hot plate (B) tests. %MPE = percentage maximum possible effect.

 
The effective dose for 50% MPE (ED50) for antinociception was calculated using the data from Figure 1 on an IBM personal computer by using the Graph Pad Inplot program (GraphPad Software, San Diego, CA). The ED50 for clonidine was 65.6 and 81.4 µg in TF and HP tests, respectively. The ED50 for ketorolac was 391 and 419 µg in the TF and HP tests, respectively.

To investigate the interaction of these two drugs, we used four different combinations (1 µg clonidine + 1 µg ketorolac; 10 µg clonidine + 10 µg ketorolac; 30 µg clonidine + 30 µg ketorolac and 150 µg clonidine + 150 µg ketorolac). When 1 µg of clonidine and 1 µg of ketorolac were injected together, no significant changes were observed because of the small initial antinociceptive effect produced by each other, but when 10 µg of clonidine plus 10 µg of ketorolac were administered, a significant decrease in clonidine-induced antinociception occurred, from 69.1 ± 7.8 to 23.5 ± 1.6 (P < 0.05) in TF and from 35.7 ± 4.7 to 4.5 ± 0.1 (P < 0.05) %MPE in HP response latency (Fig. 4). This significant (P < 0.05) antagonism was also noticed in both the TF and HP tests when 30 µg of clonidine and 30 µg of ketorolac were injected together (Fig. 4), but when the larger dose (150 µg) of both was administered, a significant antagonism was only observed in the TF, but not in the HP test (Fig. 4).



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  		Figure 4. Effect of intrathecal ketorolac (K; 1–150 µg), clonidine (C; 1–150 µg), or together (clonidine plus ketorolac; C+K) induced antinociception in the tail flick (A) and hot plate (B) tests. %MPE = percentage maximum possible effect.

 
To investigate whether clonidine- and ketorolac-induced antinociception was produced by their interaction with the spinal opioid receptors, we used naloxone, an opioid receptor antagonist. The intrathecal injection of 100 µg of naloxone had no effect on the basal antinociception (Fig. 5). Naloxone significantly abolished (P < 0.05) clonidine (150 µg)-induced antinociception only in the HP test, but not in the TF test (Fig. 5). The ketorolac (600 µg)-induced antinociceptive effect was also abolished significantly (P < 0.05) by naloxone in the TF test (Fig. 5).



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  		Figure 5. Effects of intrathecal naloxone on the antinociception produced by clonidine (150 µg) (A) and ketorolac (600 µg) (B) in the tail flick and hot plate (hind paw lick) tests. Naloxone (100 µg) was administered intrathecally 15 min before the injection of these drugs. %MPE = percentage maximum possible effect.

 
Because naloxone reduced the induction of antinociception by clonidine and ketorolac, we were interested in determining the involvement of spinal opioid receptors in the mechanism of action of these drugs. To investigate the potential of clonidine and ketorolac to bind to opioid receptors, binding studies were done by using rat spinal opioid receptors. Morphine, a powerful opioid agonist, can displace [3H]-naloxone from all opioid receptors, and [3H]-DAMGO, [3H]-DSLET and [3H]-EKC from µ, {delta}, and {kappa}-receptors, respectively (3). We assessed the ability of clonidine and ketorolac to displace [3H]-naloxone, [3H]-DAMGO, [3H]-DSLET, and [3H]-EKC from the spinal cord opioid receptors as shown in Figure 6. Morphine inhibited the specific binding of [3H]-naloxone, [3H]-DAMGO, [3H]-DSLET, and [3H]-EKC and the 50% inhibitory concentrations were 2.9 ± 0.3, 1.5 ± 0.3, 13.7 ± 2.7, and 14.4 ± 4 nM, respectively. Compared with these values, 50% inhibitory concentrations for both clonidine and ketorolac to displace opioid ligands from their receptors were over 1 million nM, indicating a lack of specific binding of clonidine and ketorolac to spinal opioid receptors. (Fig. 6).



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  		Figure 6. Effect of morphine (A), clonidine (B), and ketorolac (C) on the binding of ligands to various subtypes of spinal opioid receptors. The concentration of ligand used was [3H]Naloxone (0.5 nM), [3H]DAMGO (1 nM), [3H]DSLET (1 nM), and [3H]EKC (2 nM).

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Clonidine has been used for the treatment of hypertension and more recently for the management of acute and chronic pain. It has been administered both epidurally and systemically to alleviate pain for postoperative patients as well as for patients suffering from chronic pain, including cancer pain (9). At doses of 700–900 µg administered epidurally, clonidine produces analgesia in patients after total knee arthroplasty or abdominal surgery. However, at these doses, clonidine also produces side effects such as hypotension, bradycardia, and sedation (9). Combining smaller doses of the drug with other analgesics may produce fewer side effects. Therefore, a small dose (150 µg) of clonidine has been given epidurally with fentanyl, morphine, and bupivacaine to increase the duration of postoperative analgesia (10). Clonidine, when added to local anesthetics such as bupivacaine and tetracaine for epidural, spinal, or peripheral block, prolongs and intensifies anesthesia for surgery. Postoperatively, a combination of epidural clonidine with opiates such as meperidine produces analgesia at a reduced dose resulting in fewer side effects (10).

We investigated whether ketorolac, a NSAID that is indicated for the management of acute pain (11,12), can promote clonidine-induced antinociception similar to opioids and local anesthetics synergy observed with clonidine. Ketorolac has also been combined with local anesthetics to promote analgesia. For example, IV regional anesthesia using ketorolac and lidocaine provides effective postoperative analgesia after ambulatory hand surgery (13,14).

This is the first study to examine the effect of ketorolac on clonidine-induced antinociception. Results indicate that both clonidine and ketorolac are effective antinociceptive drugs when given alone intrathecally to rats (Fig. 1–4). However, ketorolac, instead of promoting, actually decreased the clonidine-induced antinociception. The opioid receptor antagonist, naloxone, was effective in preventing both clonidine and ketorolac-induced antinociception, suggesting an involvement of the opioid system.

The interaction between opioids and {alpha}2-adrenoreceptors has been suggested previously (15). However, we did not observe evidence of a direct interaction of clonidine or ketorolac with opioid receptors (Fig. 6). We believe that clonidine- and ketorolac-induced antinociception may involve the opioid system indirectly through the release of opioid peptides. Clonidine has been reported to induce the release of ß-endorphin from rat pars distalis (16,17) and in hypertensive patients (18). It has been suggested to induce the release of met-enkephalin in the cat spinal cord (19). It has been further suggested that the clonidine-induced released met-enkephalin could be involved in the inhibition of nociceptive transmission by inhibiting the release of substance P (19). Therefore it appears that naloxone may inhibit clonidine-induced antinociception by blocking the effect of clonidine-induced released met-enkephalin on opioid receptors (20). It is likely that a similar mechanism may be involved in the inhibition of ketorolac-induced antinociception by naloxone, because it has been reported that ketorolac also causes the release of met-enkephalin in rats (21).

It is not clear how ketorolac could inhibit clonidine-induced antinociception. Initially, ketorolac was thought to be a potent inhibitor of cyclooxygenase (COX-1), thus inhibiting the synthesis of prostaglandins (22). Because prostaglandins inhibit endogenous pain control mechanism by blocking the transmission of spinal noradrenergic synapses (23), we expected that ketorolac would enhance clonidine-induced antinociception by inhibiting the synthesis of prostaglandins that cause pain. However, we observed that, in fact, ketorolac inhibits clonidine-induced antinociception. Ketorolac may be no more potent than indomethacin or diclofenac sodium in inhibiting COX-1 or COX-2, and yet unknown mechanism(s) might contribute to the analgesic actions of ketorolac (24).

Aley and Levine (25) examined the interactions among three classes of antinociceptive agents (µ-opioid, {alpha}2-adrenergic, and A1-adenosine) in the development of tolerance and dependence to their antinociceptive effects measured by determining the degree of inhibition of prostaglandin E2-induced mechanical hyperalgesia by using the paw-withdrawal test. They reported that although DAMGO (µ-opioid receptor agonist), clonidine ({alpha}2-adrenergic receptor agonist), and CPA (A1-adenosine receptor agonist) administered alone produce antinociception, µ, A1, and {alpha}2 receptors may not act independently, but may require the physical presence of the other receptors to produce antinociception by any one agonist. Aley and Levine (25) observed that the {alpha}2 antagonist blocked not only the antinociception produced by {alpha}2 agonists but also that produced by A1 and µ agonists. Furthermore, both µ1 and A1 antagonists blocked the antinociception produced by {alpha}2 agonists. They proposed that there is a µ, A1, {alpha}2 receptor complex mediating antinociception in the periphery. It is not known whether ketorolac or similar NSAIDS interact with the µ1-, A1-, {alpha}2-receptor complex.

In summary, we observed that clonidine and ketorolac, when administered intrathecally, are potent antinociceptive drugs. Their antinociceptive effect is blocked by naloxone, which may oppose the effects of opioid peptides released by the administration of clonidine or ketorolac. Inhibition of clonidine-induced antinociception by ketorolac should be considered when both drugs are used together to alleviate pain.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication January 31, 2000.




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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