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Anesth Analg 2000;90:1146-1151
© 2000 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MEDICINE

Antinociceptive Action of Epidural K+ATP Channel Openers via Interaction with Morphine and an {alpha}2- Adrenergic Agonist in Rats

Toshio Asano, MD, Shuji Dohi, MD, and Hiroki Iida, MD

Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Gifu City, Japan

Address correspondence to Shuji Dohi, MD, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, 40 Tsukasamachi, Gifu City, Gifu 500-8705, Japan. Address e-mail to shu-dohi{at}cc.gifu-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Potassium (K+) channels may play some role in the analgesic actions of µ-opioid agonists and {alpha}2-adrenergic agonists ({alpha}2 agonists). We examined whether the adenosine triphosphate-sensitive K+(K+ATP) channel openers, levcromakalim and nicorandil, (given epidurally), might have antinociceptive effects in a tail flick test in adult male Sprague-Dawley rats implanted with a lumbar epidural catheter. The interactions with morphine and an {alpha}2 agonist were also examined. The epidural administration of levcromakalim (10 µg, 100 µg) or nicorandil (10 µg, 100 µg) alone did not produce antinociception, but 100 µg levcromakalim or nicorandil did potentiate the antinociceptive effect induced by epidural morphine. Epidural glibenclamide (10 µg), a K+ATP channel blocker, or naloxone (10 µg) antagonized this potentiation. Systemic administration of levcromakalim or nicorandil (at the same dose as that given into the epidural space) did not potentiate the epidural morphine-induced analgesia. A combination of epidural dexmedetomidine (1 µg) and morphine (1 µg) (each at a subantinociceptive dose) had a significant antinociceptive effect, and epidural glibenclamide (10 µg) partly antagonized this antinociception. These data suggest that levcromakalim and nicorandil potentiate the analgesic action of both morphine and dexmedetomidine, probably via an activation of K+ATP channels at the spinal cord level.

Implications: Epidural administration of adenosine triphosphate-sensitive potassium channel openers potentiated the analgesic actions of morphine and an {alpha}2-adrenergic agonist, presumably via activation of adenosine triphosphate-sensitive potassium channels at the spinal cord level.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The adenosine triphosphate-sensitive potassium (K+ATP) channel, originally identified in cardiac cells (1), is present in various other cells (2–4), including central nervous system neurones (5,6). This channel’s activity is blocked by sulfonylureas, such as glibenclamide, and activated by K+ATP channel openers, such as levcromakalim and nicorandil. Although no definitive description of the role that K+ATP channel activity plays in nociceptive processing has been described, there have been several experimental reports suggesting that K+ATP channels play some role in pain modulation. Salter and Henry (6) showed that inhibitory postsynaptic potentials induced by vibration-sensitive primary afferent fibers were blocked by K+ATP channel blockers in nociceptive spinal dorsal horn neurones; intracellular injection of ATP or the extracellular administration of glibenclamide modulated this effect, suggesting that K+ATP channels play some role in mediating these inhibitory postsynaptic potentials. Other reports have demonstrated, first, that the opening of K+ channels in the neuronal cell membrane is the key mechanism underlying the inhibitory effect of opioids on their target neurones (7), second, that the intrathecal administration of K+ATP channel openers produces antinociception (8), and last, that intracerebroventricular (ICV) administration of K+ATP channel openers can potentiate morphine-induced analgesia (9). In addition, K+ channels affect the action of {alpha}2-adrenergic agonists ({alpha}2 agonists), which are important drugs in the production of spinal analgesia (10). Perhaps epidurally administered K+ATP channel openers could interact in some way with the actions of {alpha}2 agonists on pain processing.

We found, in a preliminary study, that epidural nicorandil, a K+ATP channel opener, potentiated the antinociception produced by epidural morphine (11). However no report has demonstrated that a more selective K+ATP channel opener, such as levcromakalim, produces antinociception at the spinal cord level when it was epidurally administrated. The purpose of our study was to determine 1) whether levcromakalim and nicorandil exert antinociceptive effects after their epidural administration, 2) whether these drugs might potentiate the analgesic effects of epidural morphine, and 3) whether activation of K+ATP channels might modulate the analgesic action of the potent {alpha}2 agonist, dexmedetomidine.


   Methods
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 Abstract
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 Methods
Results
 Discussion
 References
 
All experimental procedures were approved by our institutional animal research committee. Male Sprague-Dawley rats weighing 350–450 g were maintained in a temperature (25°C)- and light (12-h light-dark schedule)-controlled environment and were housed individually with free access to food and water.

To reduce the influence of handling on nociceptive responses, all animals were habituated daily to the laboratory environment and trained in the test situation before epidural catheterization. For epidural catheterization, anesthesia was induced by placing the rat in a closed box containing 4% halothane in oxygen. After it lost consciousness, each rat was anesthetized by intraperitoneal administration of pentobarbital (50 mg/kg), and the skin of the back was shaved in the thoracolumbar region, a 10% povidone-iodine being applied to prevent infections. After a midline incision (3-cm long in the T8-L1 region), and a laminectomy at T12, a catheter (PE-10; 15-cm long with an approximate volume of 15 µL; Natsume Co. Ltd., Tokyo, Japan) was inserted into the epidural space under direct visual control, then advanced 2 cm caudally so that the tip lie at about the L1-2 spinal level. Surgical glue ({alpha} cyanoacrylate; Aron-{alpha}, Toagosei, Tokyo, Japan) was applied over the site of the laminectomy. The catheter was exteriorized through a second skin incision in the midline over the upper cervical area, and the free end was plugged with a stainless steel insert. After the cervical portion of the catheter had been fixed to the fascia of the neck muscles, the skin incision was closed. Benzylpenicillin potassium 0.4 mL (20000 units) was injected IM. After the surgery, each rat was allowed 7 days to recover before the study commenced. To confirm correct positioning of the distal end of the catheter (in the epidural space, not in the intrathecal space), we checked the rat’s respiratory condition after the injection of 2% lidocaine (150 µL) through the catheter. An injection of 2% lidocaine (150 µL) arrests the respiration of the rat when given intrathecally, but not epidurally. Any animals exhibiting signs of a neurological or motor deficit were eliminated from the study. Each animal received one or eight of the drugs tested, with an interval of 2 to 4 days being allowed before the next drug was tested. One hundred eight rats were instrumented during the course of this investigation. Fifteen rats were excluded because of neurological deficits. After completion of drug testing, bromphenol blue was injected so that catheter-positioning in each rat could be verified by postmortem examination of the spinal cord.

We assessed the thermal nociceptive response by using a custom-made tail-flick apparatus. This features a variable-intensity, 50-W quartz projector bulb (focused about 2 cm from the upper side of the tail) and a photodetector-automatic timer. Latency to a response was taken as the interval between the onset of the radiant heat stimulus (applied to the tail approximately 5 cm from the tip) and a visible twitch or flick. Light intensity was adjusted to yield a mean baseline latency of 3–4 s, and the automatic cutoff was set at 10 s to avoid damage to the tail. After determination of baseline values, one of the following was administered by single or multiple (5 min between one drug and the next) bolus epidural injection as indicated Table 1. The test compounds were dissolved in sterilized normal saline (morphine, naloxone, and dexmedetomidine) or 10% dimethyl sulfoxide (DMSO) (levcromakalim, nicorandil, and glibenclamide). All drug injections were given in a volume of 50 µL (administered manually for 60 s), followed by a 15-µL flush with normal saline. The baseline values were determined after the injection of normal saline or 10% DMSO. Postdrug values were measured at 5, 10, 20, 30, and 60 min after the last drug injection. We could not test doses of levcromakalim or nicorandil larger than 100 µg (the maximum concentration that would fully dissolve in 50 µL of 10% DMSO, this being a concentration of DMSO that did not induce any effect or antinociception in our pilot study). When a larger volume was injected at once (e.g., more than 200 µL) into epidural space, it tended to cause motor disturbance. So we could not determine 50% effective doses of levcromakarim and nicorandil. To examine the systemic effects of levcromakalim or nicorandil, the larger epidural dose of these drugs (100 µg) was injected IM in each rat after the epidural administration of morphine 1 µg (n = 6). In this experiment, baseline values were determined after a combination of an IM injection of 10% DMSO 200 µL and an epidural injection of normal saline 50 µL.


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  		Table 1. Drugs (Alone or Combination)
 
Tail flick latency was converted to percentage maximum possible effect (%MPE) = (postdrug value - baseline value)/(cutoff value - baseline value) x 100. The area under the time-effect curve (AUC) was calculated for each rat for a 60-min period by accumulating the effect (%MPE) measured at fixed time intervals by using the trapezoidal integration method. %AUC was calculated using the following formula: %AUC = AUCt/AUCmax x 100, where AUCt is the AUC for a given treated rat and AUCmax is the AUC for maximum possible antinociception (10 s being used for each determination). %MPE and %AUC data were presented as group mean ± SEM. Differences in %AUC among groups were analyzed by using a nonparametric statistical test (Kruskal-Wallis rank test) followed by the Mann-Whitney U-test. A P value of < 0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Epidural administration of levcromakalim or nicorandil alone, at a dose of 10 µg or 100 µg, did not cause a significant prolongation of tail flick latency. In the time-effect curve, the maximum value for %MPE achieved with levcromakalim was approximately 30%, whereas with nicorandil the %MPE did not exceed 20% at any time during the experiment (Fig. 1). Epidural glibenclamide, 10 µg, produced slight hyperalgesia (average value for %MPE = -9.4 ± 3.5). Epidural naloxone, 10 µg, produced a slight hyperalgesic effect (average value for %MPE = -4.3 ± 2.3).



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  		Figure 1. Time-course effects of changes in %MPE (percentage maximum possible effect in the tail flick test) after the epidural administration of levcromakalim (LCRK) (A; n = 8) or nicorandil (NICO) (B; n = 6) in rats. Data are presented as mean ± SEM.

 
At 1 µg, neither morphine nor dexmedetomidine induced an apparent antinociceptive effect. The epidural administration of levcromakalim 100 µg or nicorandil 100 µg potentiated the antinociceptive effect of epidural morphine (Figure 2, A and B). The epidural injection of levcromakalim 100 µg or nicorandil 100 µg produced a left-shift in the dose-response curve for morphine, although nicorandil significantly increased the antinociceptive effect of epidural morphine only for the 1-µg dose of morphine (Figure 2 C). This potentiation was significant for both drugs at 1 µg of morphine. Epidural glibenclamide (10 µg) produced a nonsignificant right-shift in the dose-response curve for morphine (Figure 2C). Epidural administration of glibenclamide (10 µg) or naloxone (10 µg) antagonized the potentiation of morphine analgesia produced by both levcromakalim and nicorandil (Figure 3). In contrast to their effects when given epidurally, IM levcromakalim 100 µg or nicorandil 100 µg did not potentiate the antinociceptive effect of epidural morphine 1 µg (Figure 3).



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  		Figure 2. Time-course of changes in percentage maximum possible effect in the tail flick test (%MPE) after epidural administration of morphine (MOR) and MOR plus levcromakalim (LCRK) (A), or MOR and MOR plus nicorandil (NICO) (B) in rats. MOR 1 µg (n = 6) or 10 µg (n = 9) with or without LCRK 100 µg, and MOR 1 µg (n = 7) or 10 µg (n = 6) with or without NICO 100 µg. Dose-response curves for tail flick antinociception produced by morphine (MOR), MOR plus LCRK, and MOR plus NICO after their epidural administration in rats (C). Epidural glibenclamide (GLIB) (10 µg) tended to right-shift in the dose-response curve for morphine. %AUC = percentage area under the time-effect curve. All data are presented as mean ± SEM *P < 0.05, **P < 0.01 versus MOR alone.

 


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  		Figure 3. Histogram showing percentage area under the time-effect curve after epidural administration (%AUC) for the following drugs: (1) levcromakalim (LCRK) or nicorandil (NICO) alone (n = 8 or 6) (2), morphine (MOR) alone (n = 6) (3), LCRK + MOR or NICO + MOR (n = 6 or 7), and (4) glibenclamide (GLIB) + LCRK + MOR or GLIB + NICO + MOR (n = 6) (5). Naloxone (NAL) + LCRK + MOR or NAL + NICO + MOR (n = 6). In addition, the effect was tested of IM injection of LCRK or NICO together with epidural injection of MOR (4th bar in each panel) (n = 6). Panels A and B show data from LCRK experiments and NICO experiments, respectively. Data are presented as mean ± SEM.

 
Morphine (1–100 µg) and dexmedetomidine (1–10 µg), given epidurally, produced a dose-dependent prolongation of tail flick latency (Figure 4A). The epidural 50% effective doses of morphine and dexmedetomidine from these dose-response curves were 24.6 ± 10.9 µg/rat, and 4.4 ± 0.79 µg/rat, respectively. Combined epidural morphine 1 µg and dexmedetomidine 1 µg had a significant antinociceptive effect, although neither morphine nor dexmedetomidine had much effect when given separately at this dose (Figure 4). This combined effect was antagonized by epidural administration of glibenclamide 10 µg (Figure 4 C).



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  		Figure 4. A, Dose-response curves for tail flick antinociception produced by morphine (MOR) or dexmedetomidine (DXM) after their epidural administration in rats. For each dose, percentage area under the time-effect curve (%AUC) was calculated from the time-effect curve for each rat for the 60 min after the injection of drug. (DXM and MOR, n = 6 for each dose) *P < 0.01 versus 1 µg. B, Time-course of changes in %MPE (percentage maximum possible effect in the tail flick test) in rats after the epidural administration of the following drugs: (1) MOR alone (2), DXM alone (3), MOR + DXM, and (4) glibenclamide (GLIB) + MOR + DXM. (n = 6 for each group). C, Histogram showing the %AUC for each rat for the 60 min after injection of drug. All data are presented as mean ± SEM.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
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References
 
The present results indicate (1) that, on epidural administration at the dosage used here, K+ATP channel openers, levcromakalim and nicorandil, did not, in themselves, produce antinociceptive effects (2). They did, however, potentiate epidural morphine-induced analgesia, and this potentiation was antagonized by epidural administration of a K+ATP channel blocker, glibenclamide. Systemic administration of levcromakalim or nicorandil at the larger of the two epidural doses did not affect epidural morphine-induced analgesia. Glibenclamide antagonized the antinociceptive effect produced by the combined administration of epidural dexmedetomidine and morphine (each at a subantinociceptive dose). These results suggest that the epidural administration of K+ATP channel openers can modulate antinociceptive mechanisms involving activation of µ-opioid receptors and {alpha}2 adrenoceptors at the spinal cord level, and that spinally administered opioids and {alpha}2 agonists produce their analgesic actions via a multifactorial mechanism involving K+ATP channels.

In 1993, Welch and Dunlow (8) reported that the intrathecal administration of three potassium channel openers produced antinociception which was blocked by glibenclamide. Since neither voltage-gated potassium channel blockers, such as tetraethylammonium and 4-aminopyridine, nor calcium-gated K+ channel blockers, such as apamin and charybdotoxin, antagonized the antinociception, they speculated that K+ATP channels might play an important role in the antinociceptive mechanism in the spinal cord.

One reason why epidural levcromakalim and nicorandil did not produce significant antinociceptive effects might be that their dosage was limited by the methodology in our study to10 and 100 µg/rat. Hence, it is possible that larger doses of these epidural K+ATP channel openers might produce antinociceptive effects. Further, because of the route for the K+ATP channel openers, perhaps a dose sufficient to produce antinociception did not reach the spinal cord tissue itself. Indeed, the dura may be a potent barrier for drugs. The meningeal permeability of drugs seems to be biphasically correlated with their octanol:buffer (pH 7.4) distribution coefficient, and the optimal value of this coefficient for maximal meningeal permeability is between 129 (e.g., alfentanil) and 560 (e.g., bupivacaine) (12). The coefficients of levcromakalim and nicorandil are approximately 18 (A. Sakuma, Smith Kline Beecham Pharmaceuticals, written communication, July 2, 1996) and 4 (N. Tatematsu, Chugai Pharmaceutical Co. Ltd., written communication, December 14, 1995), respectively, both values being well outside the optimal range for effective penetration of the spinal meninges. This could be one factor in the failure of epidural levcromakalim and nicorandil to produce antinociceptive effects at 10 and 100 µg/rat.

There have been several reports suggesting that K+ATP channel activity is closely connected with the analgesic action of morphine. K+ATP channel openers potentiate (9,13,14), whereas K+ATP channel blockers inhibit morphine-induced analgesia (8,15,16). Because the order of potency obtained for the antagonism of morphine antinociception was identical to that obtained for a block of K+ATP channels in neurones (15), these channels would appear to play an important role in µ-opioid antinociception. However, the association between opioids and K+ATP channels may be complicated, because neither the antinociceptive effect of the µ-opioid, fentanyl (13), nor that of the {kappa}-opioid receptor stimulant, U50488H (15), was blocked by a K+ATP channel blocker.

Ocana et al. (14) made a similar observation with cromakalim and U50488H in mice. The main factor in the inhibition of neuronal activity by K+ATP channel openers appears to be a hyperpolarization caused by K+ efflux (which is assumed to close voltage-gated Ca2+ channels (17). Because levcromakalim and nicorandil given epidurally, but not systemically, significantly potentiated the antinociceptive effect of epidural morphine, this potentiation was antagonized by a K+ATP channel blocker and a opioid antagonist. With this in mind, we speculate that the potentiation of epidural morphine analgesia by K+ATP channel openers is produced via cell membrane hyperpolarization as a result of the opening of the neuronal K+ATP channels, and that this could modulate morphine’s action on cell membranes in the spinal cord. However, because K+ATP channel openers may alter cerebrovascular or meningeal permeability, perhaps they might modify morphine’s pharmacokinetics, and they could modulate the activities of intracellular second messengers, such as calcium.

Activation of K+ATP channels is involved in the antinociceptive effect of the {alpha}2 agonists (14,18,19), which produce sedation and analgesia. By using mice, it has been reported that K+ATP channel openers minoxidil (ICV), pinacidil (ICV), and diazoxide (per os) potentiated the antinociception produced by subcutaneous clonidine, whereas the K+ATP channel blocker gliquidone (ICV) prevented subcutaneous clonidine-induced analgesia (18), and that the antinociceptive effect of subcutaneous clonidine was antagonized by gliquidone (ICV), but not by 4-aminopyridine (ICV) or tetraethylammonium (ICV) (19). The order of potency of sulfonylureas in antagonizing clonidine-induced antinociception was gliquidone > glipizide > glibenclamide > tolubutamide, which is the same rank order of potency as for the blockade of K+ATP channels by these drugs in neurones of the central nervous system (19). Ocana et al. (15,19) suggested that an opening of K+ATP channels was involved in the antinociceptive effect of this {alpha}2 agonist, and our results in rats agree.

When drugs (such as µ-opioids, {alpha}2 agonists, and K+ATP channel openers) are given epidurally, the possible mechanisms, sites of action, and pharmacokinetics are more complicated than when they are given intrathecally. Epidurally administered drugs can enter the neuraxis by directly crossing the dura and passing through the perineurium of the mixed spinal nerves and/or by uptake into the spinal segmental arteries or epidural veins. The lipid solubility of a given drug affects its meningeal permeability (12). Because many other factors may affect drug action via the epidural route (20), one cannot be sure that K+ATP channel openers, when injected directly into the vicinity of central nervous system neurones, would have a potent antinociceptive effect (8,9). From a toxicological point of view, it is crucial to know whether any drug administered in the vicinity of the neuronal surface will affect local blood flow. When morphine is injected into the spinal subarachnoid space, spinal cord blood flow remains unaffected (21). In contrast, {alpha}2 agonists (22,23) and K+ATP channel openers (24) are known to affect the diameter of cerebral pial vessels. Because K+ATP channel openers administered epidurally may be in a large concentration close to the spinal cord neuronal tissue that normally has a marginal blood flow, their effects on spinal cord blood flow should be investigated.

On epidural administration, the K+ATP channel openers, levcromakalim and nicorandil, both potentiated epidural morphine-induced analgesia. A combination of epidural dexmedetomidine and morphine significantly increased the analgesic effect, which was itself antagonized by K+ATP channel blockade. These data suggest that the opening of K+ATP channels could play some role in the antinociceptive effects of both µ-opioid and {alpha}2 agonists. Moreover, with the provisos mentioned above, the effects demonstrated here with K+ATP channels openers hold out the hope of a possible new modality in pain treatment.


   Acknowledgments
 
Supported by Grant-in-Aid for Scientific Research No. 11307027 (Ministry of Education, Science and Culture, Japan).


   Footnotes
 
Presented in part at the annual meeting of American Society of Anesthesiologists, New Orleans, LA, October 19–23, 1996, and at the 44th annual meeting of the Japan Society of Anesthesiology, Nigata, Japan, April 23–25, 1997.


   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 and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press