Intrathecal cyclooxygenase inhibitor administration attenuates morphine antinociceptive tolerance in rats.
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 micrograms 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 micrograms. 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 coadministered 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.
Wong
C S
CS
Department of Anesthesiology, National Defense Medical Center, Taipei, Taiwan.
Hsu
M M
MM
Chou
R
R
Chou
Y Y
YY
Tung
C S
CS
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance; D007213:Indomethacin / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009578:Nitrobenzenes / Q000494:pharmacology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology
D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D009020:Morphine; D007213:Indomethacin