Is the sulphonamide radical in the celecoxib molecule essential for its analgesic activity?
In a model of peripherally induced inflammatory pain in rats, selective inhibitors of cyclooxygenase (COX)-2 raised nociceptive thresholds above basal values, an effect referred to as "hypoalgesia". However other, non-selective, inhibitors of COX (indomethacin, piroxicam) or a selective inhibitor of COX-1 did not induce hypoalgesia in this model, implying that COX inhibition was not causally related to the hypoalgesic effect. Here, we have assessed whether other COX-2 inhibitors or other sulphonamides, apart from celecoxib could exhibit hypoalgesia in our model of inflammatory pain. Inflammation was induced in one hind paw of rats by intraplantar injection of carrageenan (250 μg). Nociceptive thresholds to mechanical stimulation were measured in the inflamed and contralateral paws for 6 h after carrageenan. Three sulphonamides, celecoxib itself, furosemide (a loop diuretic), acetazolamide (a carbonic anhydrase inhibitor), or a selective COX-2 inhibitor lacking the sulphonamide group, lumiracoxib, were injected s.c., 30 min before the pro-inflammatory stimulus. Naltrexone, a non-selective opioid antagonist was also administered s.c., 30 min before test drugs. Furosemide and acetazolamide dose-dependently induced hypoalgesia in the inflamed paw, as did celecoxib. However, lumiracoxib only produced anti-hyperalgesia. Pre-treatment with naltrexone completely prevented the hypoalgesia induced by the sulphonamides, but only partially prevented the anti-hyperalgesic effect of lumiracoxib. Taken together, our results suggest that the sulphonamide group in the structure of celecoxib is more critical for the development of hypoalgesia in our model than its ability to inhibit COX-2. Further, other sulphonamides lacking significant COX inhibition were also able to exhibit hypoalgesic effects, mediated by the endogenous opioid system.
Gassani
Beatriz Carvalho Andraus
BC
Laboratory of Inflammation and Pain, Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Rezende
Rafael Machado
RM
Paiva-Lima
Patrícia
P
Ferreira-Alves
Dalton L
DL
dos Reis
Webster Glayser Pimenta
WG
Bakhle
Y S
YS
de Francischi
Janetti Nogueira
JN
D000086:Acetazolamide / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D004008:Diclofenac / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D009292:Narcotic Antagonists; D011720:Pyrazoles; D013449:Sulfonamides; D004008:Diclofenac; D009271:Naltrexone; D000068579:Celecoxib; D000086:Acetazolamide; C473384:lumiracoxib