Intrathecal cyclooxygenase inhibitor administration attenuates morphine antinociceptive tolerance in rats

Abstract

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.

COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia

“…Tolerance to the analgesic effect of opioids is believed to be mediated at least partly by prostaglandin-mediated mechanisms (Powell et al, 1999). Intrathecal administration of COX-2 inhibitors attenuates the development of tolerance to morphine (Wong et al, 2000). Further, intrathecally administered COX-2 inhibitors have significant analgesic activity in hyperalgesic states not associated with inflammation, possibly by modulation of COX-2 that is constitutively expressed in the spinal cord (Svensson and Yaksh, 2002).…”

“…On the other hand, prostaglandins are also implicated in processing pain (Malmberg and Yaksh, 1992;Julius and Basbaum, 2001;Samad et al, 2001). Indeed, COX-2 inhibitors inhibit the development of morphine tolerance (Wong et al, 2000).…”

D1 Dopamine Receptors Modulate ΔFosB Induction in Rat Striatum after Intermittent Morphine Administration

“…Morphine-induced cFos expression in the striatum is attenuated by the AMPA receptor antagonist, GYKI-52466 . The development of morphine antinociceptive tolerance is attenuated after intrathecal administration of roscovitine, a Cdk5 inhibitor (Wang et al, 2004). In another report, acute morphine administration increases the levels of Cdk5 in rat cortex, whereas a 40% decrease in Cdk5 protein levels is seen after 5-day escalating dose morphine administration (Ferrer-Alcon et al, 2003).…”

Disruption of δ-opioid receptor phosphorylation at Threonine 161 attenuates morphine tolerance in rats with CFA-induced inflammatory hypersensitivity

“…Evidence shows that intrathecal administration of roscovitine, an inhibitor of Cdk5, has an antinociceptive effect, while co-administration of roscovitine and morphine enhances the antinociceptive effect of morphine in tolerant rats [33] .…”