Spinal antinociceptive effects of cyclooxygenase inhibition during inflammation: Involvement of prostaglandins and endocannabinoids.
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.
Telleria-Diaz
Alejandro
A
Department of Physiology, University Hospital of Jena, Teichgraben 8, D-07740 Jena, Germany Department of Biochemistry, University Hospital of Jena, Nonnenplan 2, D-07740 Jena, Germany.
Schmidt
Martin
M
Kreusch
Stefan
S
Neubert
Anne-Kathrin
AK
Schache
Florian
F
Vazquez
Enrique
E
Vanegas
Horacio
H
Schaible
Hans-Georg
HG
Ebersberger
Andrea
A
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005989:Glycerides / Q000378:metabolism*; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use; D007278:Injections, Spinal / Q000379:methods; D007719:Knee Joint / Q000473:pathology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010147:Pain Measurement; D010812:Physical Stimulation / Q000379:methods; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D018709:Statistics, Nonparametric
D001095:Arachidonic Acids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D007189:Indans; C093700:L 745337; D010880:Piperidines; D011720:Pyrazoles; C115461:SC 560; C103505:AM 251; C094503:glyceryl 2-arachidonate; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone