British Journal of Anaesthesia, 2000, Vol. 85, No. 5 747-751
© 2000 The Board of Management and Trustees of the British Journal of Anaesthesia
Intrathecal cyclooxygenase inhibitor administration attenuates morphine antinociceptive tolerance in rats
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
Several lines of evidence suggest that the N-methyl-D-aspartate receptor (NMDA) and nitric oxide (NO) systems are involved in morphine tolerance. Cyclooxygenase (COX) inhibitors may also play a role in morphine tolerance by interacting with both systems. In the present study, we examined the effects of the COX inhibitors N-(2-cyclohexyloxy-4-nitrophenyl) methanesulphonamide (NS-398, selective COX2 inhibitor) and indomethacin (non-selective COX inhibitor) on the development of antinociceptive tolerance of morphine in a rat spinal model. The antinociceptive effect was determined by the tail-flick test. Tolerance was induced by injection of morphine 50 µg intrathecally (i.t.) twice daily for 5 days. The effects of NS-398 and indomethacin on morphine antinociceptive tolerance were examined after administering these drugs i.t. 10 min before each morphine injection. Neither NS-398 nor indomethacin alone produced an antinociception effect at doses up to 40 µg. NS-398 and indomethacin did not enhance the antinociceptive effect of morphine in naïve and morphine-tolerant rats. However, they shifted the morphine antinociceptive dose–response curve to the left when co-administered with morphine during tolerance induction, and reduced the increase in the ED50 of morphine (dose producing 50% of the maximum response) three- to four-fold. Collectively, these findings and previous studies suggest that COX may be involved in the development of morphine tolerance without directly enhancing its antinociceptive effect.
Br J Anaesth 2000; 85: 747–51
* Corresponding author: Department of Anesthesiology, National Defense Medical Center and Tri-Service General Hospital, #8 Section 3, Tingchow Road, Taipei, Taiwan
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