1Department of Anesthesiology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan. 2School of Biological Sciences, University of California, Irvine, Irvine, California 92697, USA. 3Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan
Accepted for publication: May 4, 2000
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Abstract |
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Br J Anaesth 2000; 85: 74751
Keywords: enzymes, cyclooxygenase inhibitors; non-steroidal anti-inflammatory drugs; analgesics opioid, morphine
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Introduction |
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There is a large body of evidence indicating the involvement of the NMDA receptor and NO systems in opioid tolerance. NMDA antagonists and NO inhibitors have been shown to attenuate or prevent morphine tolerance.714 Recently, we further demonstrated that NMDA receptor antagonists inhibit morphine tolerance not only by modulating the binding characteristics of µ-opioid receptors11 but also by partially preventing the constitutive neuronal expression of NO synthase (NOS).14
Mao et al. proposed that opioid tolerance and neuropathic pain syndromes share a common intracellular mechanism; both are expressed as a loss of analgesic effect of opioids.15 In addition, Malmberg and Yaksh reported that NSAIDs could attenuate the hyperalgesia mediated by glutamate receptors.16 Interaction between NMDA- and PG receptor-mediated events during inflammatory nociception has also been reported.17 PGE2 was shown to stimulate the release of NO from rat spinal cord by NMDA receptor activation through EP1 receptors.18 Moreover, cross-communication between the NOS and COX systems has also been demonstrated.19 20 NO interacts directly with COX to enhance its enzymatic activity.19 Inducible NOS activation may increase NO release and subsequently increase PG release, via COX activation.20 These findings imply complicated interactions among NMDA receptors and the NO and COX systems. In the light of these findings, we propose that COX inhibitors modulate antinociceptive tolerance of morphine via interaction with the NMDANO system. The present study was designed to examine the effects of the COX-selective inhibitors NS-398 (a selective COX2 inhibitor) and the non-selective COX inhibitor indomethacin on the development of morphine antinociceptive tolerance in a rat spinal model.
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Materials and methods |
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In a preliminary study, the effect of 30 µg of NS-398 or indomethacin, alone or with morphine, was not significantly different from that of of 20 µg in the tail-flick test. Therefore, a dose of 20 µg (i.t.) was used for NS-398 and indomethacin in the present study. Tolerance to the antinociceptive effect of morphine was induced by injection of morphine (50 µg, i.t.) twice daily for 5 days. To investigate the effects of COX inhibitors (NS-398 and indomethacin, 20 µg) on morphine tolerance, we calculated the ED50 for morphine antinociception after morphine tolerance had developed. The COX inhibitors were administered 10 min before each morphine injection on each of the 5 days of tolerance induction. The effects of COX inhibitors on the morphine antinociceptive doseresponse curve were examined on the first and fifth days of tolerance induction. The tail-flick test was performed daily.
The tail-flick response was converted from a defined latency to the maximum per cent effect (MPE) as follows:
NS-398 and indomethacin (Cayman, MI, USA) were dissolved in dimethyl sulphoxide (DMSO) and saline (1:1). DMSO had no significant effects on antinociception using the tail-flick test.21
The morphine antinociceptive doseresponse latency was analysed by computer-assisted linear regression (Cricket Graph 1.32; Islandia, NY, USA). The ED50 was defined as the morphine dose that induced a 50% MPE measured by the tail-flick test and was calculated using the linear regression equations. All data are presented as mean and SEM. The data were subjected to analysis of variance and the Dunnett test, and P values <0.05 were considered significant.
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Results |
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Discussion |
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We found that a selective and a non-selective inhibitor of COX attenuated morphine antinociceptive tolerance. This is consistent with a recent study showing that the non-selective COX inhibitors ketorolac and ibuprofen inhibited the development of morphine tolerance.22 The morphine-tolerant rats had lower mean baseline tail-flick latency than the control group, suggesting that thermal hyperalgesia may develop in association with the development of morphine tolerance.10 15 It is interesting that COX2 is not only inducibly expressed after the inflammation process but is also constitutively expressed in the spinal cord of normal rats.2325 Furthermore, COX2 is distributed in the superficial layer of the dorsal horn and is related to spinal nociceptive processing in the normal condition.25 However, it is not clear which COX isoforms are involved in morphine tolerance in the rat spinal cord. The effects of NS-398, a COX2-selective inhibitor, on morphine tolerance and morphine ED50 values were slightly greater than those of indomethacin, implying that the inhibition of COX2 may play a role in the development of morphine tolerance. Moreover, the present results agree with those of previous reports showing that COX inhibitors did not produce any thermal antinociceptive effects in the tail-flick test.21 26 Although the non-selective COX inhibitor ketorolac has been shown to potentiate the analgesic effects of opioids by modulating the function of the opioid receptor in visceral nociception5, the present results demonstrate that NS-398 and indomethacin did not potentiate morphine antinociception either before or after the development of morphine tolerance. However, these data also confirm that neither COX1 nor COX2 was directly involved in phasic thermal nociceptive transmission in the rat spinal cord.26
Our previous studies have demonstrated that several drugs attenuate morphine tolerance and maintain the antinociceptive efficacy of morphine in a rat spinal model.11 14 Although the non-selective COX inhibitor ketorolac has been shown to potentiate the analgesic effect of opioids by modulating opioid receptor function in visceral nociception,5 in the present study neither NS-398 nor indomethacin potentiated morphine antinociception, either before or after the development of morphine tolerance. We found previously that the NMDA receptor antagonist MK-801 attenuated morphine tolerance by preventing the reduction of high-affinity µ-opioid receptor sites.11 14 In the present study, COX inhibitors were found to attenuate morphine tolerance but did not enhance the antinociceptive effect of morphine. Because NMDA receptor antagonists and COX inhibitors shift the morphine doseresponse curve in different directions, our present results suggest that COX inhibitors inhibit PG synthesis and related neurotransmission rather than having a direct inhibitory effect on conformational change of the µ-opioid receptor.
In summary, the present results show that COX inhibitors can attenuate the development of morphine tolerance. However, both the non-selective COX inhibitor indomethacin and COX2 inhibitors failed to produce any analgesic effects or potentiation of morphine antinociception either before or after the development of morphine tolerance. Which isoforms of COX are expressed and what interactions occur among the NMDA, NO and COX systems during morphine tolerance in the spinal cord are worthy of further investigation.
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Acknowledgements |
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Footnotes |
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References |
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