Spinal antinociceptive effects of cyclooxygenase inhibition during inflammation: Involvement of prostaglandins and endocannabinoids

Abstract

Both cyclooxygenase-1 and -2 are expressed in the spinal cord, and the spinal COX product prostaglandin E(2) (PGE(2)) contributes to the generation of central sensitization upon peripheral inflammation. Vice versa spinal COX inhibition is considered an important mechanism of antihyperalgesic pain treatment. Recently, however, COX-2 was shown to be also involved in the metabolism of endocannabinoids. Because endocannabinoids can have analgesic actions it is conceivable that inhibition of spinal COX produces analgesia not only by inhibition of PG synthesis but also by inhibition of endocannabinoid breakdown. In the present study, we recorded from spinal cord neurons with input from the inflamed knee joint and we measured the spinal release of PGE(2) and the endocannabinoid 2-arachidonoyl glycerol (2-AG) in vivo, using the same stimulation procedures. COX inhibitors were applied spinally. Selective COX-1, selective COX-2 and non-selective COX inhibitors attenuated the generation of spinal hyperexcitability when applied before and during development of inflammation but, when inflammation and spinal hyperexcitability were established, only selective COX-2 inhibitors reversed spinal hyperexcitability. During established inflammation all COX inhibitors reduced release of spinal PGE(2) almost equally but only the COX-2 inhibitor prevented breakdown of 2-AG. The reversal of spinal hyperexcitability by COX-2 inhibitors was prevented or partially reversed by AM-251, an antagonist at the cannabinoid-1 receptor. We conclude that inhibition of spinal COX-2 not only reduces PG production but also endocannabinoid breakdown and provide evidence that reversal of inflammation-evoked spinal hyperexcitability by COX-2 inhibitors is more related to endocannabinoidergic mechanisms than to inhibition of spinal PG synthesis.

Signaling pathways of ATP‐induced PGE2 release in spinal cord astrocytes are EGFR transactivation‐dependent

“…The spinal COX product PGE2 contributes to the generation of central sensitization upon peripheral inflammation (Telleria-Diaz et al, 2010). Given evidence that inhibition of PGE2 release can reduce behavioral signs of pain after SCI (Hains et al, 2001) and peripheral nerve injury (McMahon et al, 2005).…”

Evaluation of the Cyclooxygenase Inhibiting Effects of Six Major Cannabinoids Isolated from Cannabis sativa

“…Interestingly, a recent report, linking COX-2 inhibition to increased endocannabinoid levels, suggests the ECS and the COX-mediated prostaglandin pathway to be closely connected. 35) In conclusion, it is clear that cannabinoids inhibit COXenzymes, but in a higher concentration range, as compared to anti-inflammatory drugs (i.e. indomethacin).…”

Involvement of Spinal CB1 Cannabinoid Receptors on the Antinociceptive Effect of Celecoxib in Rat Formalin Test

“…IT pretreatment with AM-251, the selective cannabinoid CB1 receptor antagonist, blocked the analgesic effects of indomethacin and flurbiprofen in animal pain models (22). The inhibition of COX-2 at the spinal cord level decreased both prostaglandin generation and endocannabinoid degradation and indicated that the endocannabinergic mechanisms was more responsible for their antinociceptive activities than the inhibition of spinal prostaglandin synthesis (39). Overall, the possible reaction pathways of celecoxib in this study are shown in Figure 4.…”