Intrathecal cyclooxygenase inhibitor administration attenuates morphine antinociceptive tolerance in rats

Several lines of evidence suggest that the N-methyl-D-aspartate receptor (N MDA) and nitric oxide (NO) systems are involved in morphine tolerance. Cycl ooxygenase (COX) inhibitors may also play a role in morphine tolerance by i nteracting with both systems. In the present study, we examined the effects of the COX inhibitors N-(2-cyclohexyloxy-4-nitrophenyl) methanesulphonamid e (NS-398, selective COX2 inhibitor) and indomethacin (non-selective COX in hibitor) on the development of antinociceptive tolerance of morphine in a r at spinal model. The antinociceptive effect was determined by the tail-flic k test. Tolerance was induced by injection of morphine 50 mug intrathecally (i.t.) twice daily for 5 days. The effects of NS-398 and indomethacin on m orphine antinociceptive tolerance were examined after administering these d rugs i.t. 10 min before each morphine injection. Neither NS-398 nor indomet hacin alone produced an antinociception effect at doses up to 40 mug. NS-39 8 and indomethacin did not enhance the antinociceptive effect of morphine i n naive and morphine-tolerant rats. However, they shifted the morphine anti nociceptive dose-response curve to the left when coadministered with morphi ne during tolerance induction, and reduced the increase in the ED50 of morp hine (dose producing 50% of the maximum response) three- to four-fold. Coll ectively, these findings and previous studies suggest that COX may be invol ved in the development of morphine tolerance without directly enhancing its antinociceptive effect.