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*Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and
Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama
Address correspondence to Igor Kissin, MD, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. Address e-mail to kissin{at}zeus.bwh.harvard.edu
Abstract
To test the role of cholecystokinin (CCK) and N-methyl-D-aspartate-nitric oxide (NMDA-NO) systems in the development of acute tolerance to analgesia during alfentanil IV infusion, we conducted experiments in rats with the use of an infusion algorithm designed to maintain a constant plasma level of the opioid for 4 h. The degree of acute tolerance was determined on the basis of decline in the level of analgesia measured with a tail compression test. CCKB receptor antagonists (proglumide, CI-988, and L-365,260) and NMDA-NO cascade inhibitors (dizocilpine and NO synthase inhibitor) were administered before the start of alfentanil infusion. Use of 30 mg/kg proglumide, 10 mg/kg CI-988, and 1 mg/kg L-365,260 attenuated acute tolerance at 1 h of alfentanil infusion by approximately 60%, 55%, and 70%, respectively, and by the end of 4-h infusion by 50%, 50%, and 25%, respectively. Use of 0.1 mg/kg dizocilpine and 10 mg/kg NG-nitro-L-arginine methyl ester attenuated acute tolerance at 1 h of alfentanil infusion by approximately 65% and 65% and by the end of 4-h infusion by 30% and 0%, respectively. Comparison of the results with CCKB receptor antagonists and inhibitors of NMDA-NO cascade demonstrates that both groups of drugs provide more or less similar degrees of attenuation of acute tolerance to the antinociceptive effect of alfentanil, and none of these drugs completely prevents tolerance development.
Implications: The mechanism of acute tolerance to the analgesic effect of alfentanil depends on participation of multiple systems of adaptation that include cholecystokininB receptors and N-methyl-D-aspartic acid-nitric oxide cascade. Drugs that inhibit function of these systems attenuate tolerance development.
It has been demonstrated that rapid development of acute tolerance to the analgesic effect of opioids occurs in rodents (1–3) and in humans (4). Acute tolerance to alfentanil given by continuous IV infusion is unexpectedly profound and rapidly developing (5). Alfentanil received renewed attention because of the introduction of computer-assisted infusion pumps designed to maintain a certain target plasma concentration of opioids during surgery and in the early postoperative period. Multiple mechanisms are involved in the development of opioid tolerance—from uncoupling of the opioid receptors from their second messengers to the adaptive changes in parallel antagonistic or facilitatory pain transmission systems (6). The multiplicity of potential adaptive mechanisms suggest tolerance to opioids could be mechanistically different under different conditions of drug administrations. For example, it was found that the effects of intermittent administration of opioids on tolerance development are completely different from those of continuous infusion (7). Profound differences in the character of tolerance development were also observed with acute-versus-chronic or spinal-versus-supraspinal opioid administration (8,9). Even relatively small differences in drug actions could have very important consequences for tolerance development. For example, Bilsky et al. (10) reported that N-methyl-D-aspartate (NMDA) receptor antagonists block the development of chronic antinociceptive tolerance to morphine, however, not to fentanyl or other selective µ- or 
-opioid agonists. Therefore, it was possible to expect that acute tolerance to alfentanil given by continuous IV infusion could have its specific underlying mechanisms.
Many systems could participate in counterbalancing the antinociceptive effect of opioids. There is convincing evidence that the cholecystokinin (CCK) system and the NMDA receptor-nitric oxide (NO) synthase system play important roles in the development of chronic tolerance to the analgesic effect of morphine. CholecystokininB receptor antagonists (proglumide, CI-988, L-365,260) antagonize tolerance to morphine (11–14). Reports (15,16) on the morphine-induced CCK release in the spinal cord confirm that CCK may function as an endogenous antiopioid and determine morphine antinociceptive tolerance. Prevention of the development of chronic morphine tolerance by NMDA receptor antagonists (17–19) and NO synthase inhibitors (20) is well established. Therefore, the NMDA-NO cascade was described as a pain facilitatory system that may participate in opioid tolerance development.
We sought to determine whether the CCK system and the NMDA-NO cascade, which determine chronic tolerance to morphine, are also involved in the development of acute tolerance to the analgesic effect of continuously infused alfentanil. With this aim, we elected to test CCK receptor antagonists (proglumide, CI-988, and L-365,260), NMDA receptor antagonist (dizocilpine), and NG-nitro-L-arginine methyl ester (L-NAME).
Methods
Experiments were performed on male Sprague-Dawley rats weighing 250–350 g. The animals were housed with a 12-h light-dark cycle, and food and water were available ad libitum. The protocol for this study was approved by the Institutional Panel on Laboratory Animal Care.
A catheter for the drug infusion was chronically implanted into the jugular vein, and its free end was exteriorized through the skin at the back of the neck. The surgical procedure for implantation was performed under 60 mg/kg intraperitoneal (IP) ketamine and 12 mg/kg IP xylazine anesthesia several days before the experiment. Alfentanil was infused with a Harvard Apparatus pump. Alfentanil infusion algorithm was based on the constants of one compartment model for rats derived from our previous study (5).
The response to mechanical noxious stimulation was determined by measuring the threshold of motor response to increasing pressure applied to the tail-tail compression test (21) with the use of an Analgesy-Meter® (Ugo Basile, Milan, Italy). The rat’s tail was positioned on a Teflon platform, and the pressure plate (0.7-mm edge) attached to this device was applied to the tail while the rat was held in the experimenter’s hand. Pressure was increased at a constant rate (cutoff pressure of 2.4 kg) until coordinated struggle occurred. Three consecutive measurements were recorded and the mean of the last two measurements was taken as the pressure threshold. For each consecutive determination of the pain threshold, the pressure plate was moved 2 mm cephalad. Measurements were made by an experimenter who did not know of expected changes in the reaction thresholds among the treatment groups.
We performed five series of experiments: proglumide, CI-988, L-365,260, dizocilpine, and L-NAME. The series consisted of several groups of 6–8 rats each. In all series, alfentanil was administered with the same pattern: a bolus dose of 50 µg/kg followed by an infusion rate of 155 µg/kg/h for 4 h. This pattern was chosen to rapidly achieve and maintain a stable alfentanil plasma concentration (5). The pressure threshold for motor response was determined before and after an interacting drug and 30, 60, 120, 180, and 240 min after the beginning of alfentanil infusion. The degree of acute tolerance was determined on the basis of decline in the level of analgesia during the infusion period. We demonstrated previously (2) that in this experimental model of tolerance the extent of the threshold decline is independent of the number of repeatedly made measurements.
The proglumide experiments were conducted in two subseries. One subseries was performed in an attempt to reproduce the results reported by Tang et al. (12) with the acute tolerance to morphine. In this subseries, proglumide was repeatedly injected during the 4-h infusion of alfentanil (four injections, one every hour, with the first injection given 10 min before the administration of alfentanil). The injections of proglumide were administered IP in 0.9% saline containing 2% Tween 80. The animals were randomly assigned to one of the following four groups: alfentanil and 15 mg/kg proglumide, IP; alfentanil and 30 mg/kg proglumide, IP; alfentanil and proglumide vehicle, IP; saline and 30 mg/kg proglumide, IP.
The other subseries with proglumide were performed after preliminary experiments in which it was found that proglumide-induced potentiation of alfentanil analgesia occurs only after the first injection of the proglumide. If one of two prealfentanil injections of proglumide is administered 1–1 h 30 min before alfentanil, the potentiation is absent. In this subseries, the animals were randomly assigned to one of two groups: alfentanil and proglumide, and alfentanil and vehicle. In the proglumide group, animals received two 30 mg/kg IP injections of the drug, one 85 min and another 15 min before alfentanil administration (no IP injections were administered during 4-h alfentanil infusion). Animals in the control group received only proglumide vehicle (two IP injections).
Because proglumide is a weak, nonselective CCK receptor antagonist, two other antagonists with high selectivity for CCKB receptors, CI-988 and L-365,260, were also used in two additional series of experiments. In the CI-988 series of experiments, the animals were randomly assigned to one of two groups: alfentanil and CI-988, and alfentanil and vehicle. The first group received an injection of 10 mg/kg IP CI-988 (in 0.9% saline containing 2% Tween 80) 10 min before the administration of alfentanil; the control group received an IP injection of the vehicle. The L-365,260 series of experiments also consisted of two groups. In one group, animals received 1 mg/kg IP L-365,260 (in 0.9% saline containing 2% Tween 80) 10 min before the administration of alfentanil; the other group received the vehicle.
Two series of experiments were related to NMDA-NO cascade—dizocilpine and L-NAME. In the dizocilpine (MK-801) series, animals were randomly assigned to one of the following four groups: alfentanil and 0.03 mg/kg dizocilpine, IV; alfentanil and 0.1 mg/kg dizocilpine, IV; alfentanil and dizocilpine vehicle, IV; saline and 0.1 mg/kg dizocilpine, IV. Dizocilpine was injected 60 min before alfentanil administration.
In the L-NAME series of experiments, 10 mg/kg IV NO synthase inhibitor (NG-nitro-L-arginine methyl ester) was administered 30 min before the administration of alfentanil. One control group received 0.9% saline instead of L-NAME, the other control group received 10 mg/kg IV L-NAME and 0.9% saline infusion instead of alfentanil.
Pressure threshold was treated as a continuous variable and analyzed by using a two-way (groups and time) analysis of variance with time treated as a repeated measure factor. Comparisons between groups at each time were performed with the use of a two-tailed unpaired Student’s t-test. Multiple comparisons among pairs of means were made by using the Fisher’s protected least significant difference method (22). Differences were declared statistically significant if P < 0.05.
Results
All three CCKB receptor antagonists attenuated the development of acute tolerance to alfentanil analgesia. In the subseries of experiments with repeated administration of proglumide during the 4-h infusion of alfentanil (n = 8 for each group), the initial analgesic effect of alfentanil tended to be greater compared with the proglumide vehicle (Figure 1). With 30 mg/kg proglumide, acute tolerance was reduced by approximately 60% both at 1 h and 2 h of the alfentanil infusion and by approximately 50% at 4 h of the infusion (compared with reduction of the initial analgesic effect in the alfentanil-vehicle group, Figure 2A). Figure 1 demonstrates that in the alfentanil-vehicle group, pressure threshold before the end of alfentanil infusion was only insignificantly greater than that before the start of infusion (644 ± 64 vs 603 ± 69 g, not significant). In the alfentanil-30 mg/kg proglumide group, pressure threshold at the end of alfentanil infusion was almost twice as high as that for baseline measurements (1211 ± 391 vs 608 ± 38 g, P < 0.01). At the same time, the development of acute tolerance was not completely prevented by proglumide; pressure threshold decreased from the peak of 1870 ± 490 to 1211 ± 391 g at 4 h (compared with baseline 608 ± 38 g, P < 0.01). In this subseries of proglumide experiments, the peak of alfentanil-induced analgesia was insignificantly larger in the alfentanil-30 mg/kg proglumide group than in the alfentanil-vehicle group (1870 ± 490 vs 1496 ± 504 g, not significant).
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In the CI-988 series of experiments (n = 6 for each group), the attenuation of acute tolerance to alfentanil was to the same degree as in the proglumide series (Figure 2A). In the L-365,260 series (n = 6 for each group), the suppression of acute tolerance to alfentanil was different from those with proglumide and CI-988 only in the lesser degree of tolerance attenuation at the end of alfentanil infusion by approximately 25% at 4 h compared with approximately 70% at 1 h of infusion (Figure 2A). Dosages of 10 mg/kg CI-988 and 1 mg/kg L-365,260 did not change pressure threshold (before and after the administration of antagonists, 665 ± 40 vs 633 ± 39 g for CI-988 and 657 ± 51 vs 657 ± 49 g for L-365,260). The peak of alfentanil-induced analgesia also was not changed by either of the two drugs.
Figure 3 demonstrates the effect of the NMDA receptor antagonist dizocilpine (n = 7 for each group). A dose of 0.1 mg/kg dizocilpine (the maximal dose that, in our experiments, did not yet produce behavioral changes that could influence pressure threshold measurements) did not increase the peak of alfentanil-induced analgesia. The attenuation of acute tolerance to alfentanil was similar to that with CCKB receptor antagonists. With 0.1 mg/kg dizocilpine, the tolerance was reduced by approximately 65% at 1 h, 50% at 2 h, and 30% at 4 h of alfentanil infusion (Figure 2B).
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All three CCKB receptor antagonists attenuated the development of acute tolerance to the antinociceptive effect of alfentanil. However, by the end of the alfentanil infusion, the degree of acute tolerance was reduced only by one half. The comparison of two proglumide subseries of experiments indicates that increase in the total dose of proglumide, by giving it every hour during alfentanil infusion, did not result in any enhancement of tolerance suppression, suggesting that it is impossible to provide complete prevention of acute tolerance by increasing the dose of CCKB receptor antagonists. At a time when the development of acute tolerance by proglumide and CI-988 was suppressed approximately to the same degree at one, two, and four hours of alfentanil infusion, the effect of L-365,260 was significantly decreased by four hours of infusion (Figure 2A). The most likely reason for this decrease was that L-365,260 is very rapidly cleared after its systemic administration; its terminal half-life in rats is only 30 minutes (23). Interestingly, proglumide, a CCK nonselective antagonist, produced the maximum inhibitory effect of the same degree as two other antagonists highly selective for CCKB receptors, indicating that CCKA receptors are not important in the outcome.
CholecystokininB receptor antagonists can attenuate the development of acute tolerance to alfentanil without enhancing the initial alfentanil-induced antinociceptive effect. In our experiments, 10 mg/kg CI-988 and 1 mg/kg L-365,260, did not change the pressure threshold measured before the administration of alfentanil, and did not increase the peak of alfentanil-induced analgesia. Although CCKB receptor antagonists enhance the analgesic effect of opioids, this effect depends on a dose. Absence of potentiation of the acute antinociceptive effect of morphine with 10 mg/kg CI-988 and 1 mg/kg L-365,260 was reported by Dourish et al. (13) and Hoffmann and Wiesenfeld-Hallin (24). With proglumide experiments, it was found that a tendency for proglumide-induced potentiation of the peak of antinociceptive response to alfentanil occurs only after the first injection of proglumide. In the second subseries of proglumide experiments, when the drug’s two injections were administered approximately an hour apart, both before the start of alfentanil infusion, the peak of the alfentanil-induced antinociceptive effect did not have a tendency for enhancement. At the same time, the development of acute tolerance to alfentanil was attenuated to the same degree as in the first proglumide subseries in which the peak of alfentanil-induced antinociception had a tendency to be enhanced by proglumide.
The development of chronic tolerance to morphine was reported to be completely prevented by CCKB receptor antagonists (13,14). Results of our experiments demonstrate that acute tolerance to the antinociceptive effect of alfentanil, even with the largest doses of CCKB receptor antagonists, cannot be completely prevented.
The attenuation of chronically induced morphine antinociceptive effects by NMDA receptor antagonists has been well described with systemic (17) and spinal (19) administration of these drugs. It was also reported that, in isolated, neonatal rat spinal cord, alfentanil induces a rapid NMDA receptor-dependent increase in neuronal excitability that may be related to acute tolerance (25), although in the same model the authors could not find any evidence for acute tolerance measured by a decrease in effectiveness over time (26). Fairbanks and Wilcox (3) demonstrated that NMDA receptor antagonists and NO synthase inhibitors, inhibit acute tolerance to spinally administered morphine. In our experiments, dizocilpine attenuated acute tolerance to the antinociceptive effect of alfentanil approximately to the same extent as that with CCKB receptor antagonists. The effect of dizocilpine on acute tolerance was without enhancement of the peak of alfentanil-induced analgesia. Some decline in the degree of tolerance suppression during alfentanil infusion (from approximately 60% at one hour to approximately 30% at four hours, P < 0.01) might be associated with a moderately short elimination half-life of dizocilpine, one to two hours in rats (27).
Bilsky et al. (10) reported that NMDA receptor antagonists blocked chronic antinociceptive tolerance to morphine, however, not to selective µ- or -agonists, including fentanyl. They concluded that block of opioid tolerance by NMDA receptor antagonists is not a general phenomenon related to all opioids. Alfentanil, used in our study, belongs to the same group of opioids. The difference in the results is probably related to the difference in the model of tolerance (chronic versus acute or intermittent versus continuous drug administration).
L-NAME attenuated acute tolerance only at one and two hours, not at four hours of the alfentanil infusion. It was the only drug in this study that did not provide effects at the end of the infusion. The short duration of the effect on tolerance is in contrast to the long-lasting effect of this drug on brain NO synthase activity. Iadecola et al. (28) reported that, in rats, 10 mg/kg IV L-NAME inhibits enzyme activity by 40%, and this effect remains stable at 8 and 24 hours. The gradual disappearance of L-NAME-induced inhibition of acute tolerance to alfentanil despite continuing inhibition of the synthase activity could be explained by the gradually increasing role of some other mechanism that, together with NO, participates in the development of acute tolerance.
Along with suppression of acute tolerance to alfentanil, L-NAME enhanced the peak of alfentanil-induced analgesia. There is evidence, however, that the analgesic actions of opioids and the development of tolerance to the analgesic effect are mediated through separate physiological mechanisms. For example, Kolesnikov et al. (29) reported that selective down-regulation (via antisense approach) of one of the NO synthase isoforms (nN0S-1) prevents the development of chronic morphine tolerance, and down-regulation of another isoform (nNOS-2) blocks morphine analgesia.
Comparison of the results with CCKB receptor antagonists (proglumide, CI-988, and L-365,260) and inhibitors of NMDA-NO cascade (dizocilpine and L-NAME) demonstrates that both groups of drugs provide more or less similar degrees of attenuation of acute tolerance to the antinociceptive effect of alfentanil, and none of these drugs completely prevents tolerance development.
Two types of pharmacodynamic mechanisms for tolerance have been suggested, a within-system adaptation and a between-system adaptation (30). In the within-system mechanism, the primary response element to the drug would itself adapt to neutralize the drug’s effect. Some receptors are designed to "turn themselves off" with continuing association with an agonist. In the between-system mechanism, adaptation could derive from another system counterbalancing the initial effect. Adaptive opposing responses could participate in the development of tolerance to opioids. Two of the multiple systems providing such responses, CCK system and NMDA-NO cascade, take part in the development of acute tolerance to the analgesic effect to alfentanil. However, other mechanisms could also contribute to the development of acute tolerance.
A study in volunteers indicates that the rapid development of tolerance to the analgesic effects of opioids observed in experimental animals also occurs in humans (4). Tolerance to analgesia observed in this study during remifentanil infusion was profound and developed rapidly. However, the degree of tolerance development in clinical pain may be different. Constant clinical pain could counteract mobilization of antianalgesia systems participating in acute tolerance, such as CCK and NMDA-NO. If the analgesic effect of opioids in postoperative pain is significantly reduced by rapidly developing tolerance, the use of CCKB receptor antagonists or inhibitors of NMDA-NO cascade could reduce opioid requirements.
Acknowledgments
Supported by National Institutes of Health grant GM35135.
We wish to thank the following manufacturers: CI-988 was a gift of Parke-Davis, Ann Arbor, MI and L-365,260 was a gift of ML Laboratories, St. Albans, Herts, UK.
References
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