Acetaminophen inhibits spinal prostaglandin E2 release after peripheral noxious stimulation.
BACKGROUND
Prostaglandin play a pivotal role in spinal nociceptive processing. At therapeutic concentrations, acetaminophen is not a cyclooxygenase inhibitor. inhibitor. Thus, it is antinociceptive without having antiinflammatory or gastrointestinal toxic effects. This study evaluated the role of spinal prostaglandin E2 (PGE2) in antinociception produced by intraperitoneally administered acetaminophen.


METHODS
The PGE2 concentrations in the dorsal horn of the spinal cord were measured after formalin was injected into the hind paw of rats. The effect of antinociceptive doses of acetaminophen (100, 200, and 300 mg/kg given intraperitoneally) on PGE2 levels and flinching behavior was monitored Spinal PGE2 and acetaminophen concentrations were obtained by microdialysis using a probe that was implanted transversely through the dorsal horn of the spinal cord at L4. Furthermore, the effects of acetaminophen on urinary prostaglandin excretion were determined.


RESULTS
Intraperitoneal administration of acetaminophen resulted in a significant decrease in spinal PGE2 release that was associated with a significant reduction in the flinching behavior in the formalin test Acetaminophen was distributed rapidly into the spinal cord with maximum dialysate concentrations 4560 min after intraperitoneal administration. Urinary excretion of prostanoids (PGE2, PGF2alpha, and 6-keto-PGF1alpha) was not significantly altered after acetaminophen administration.


CONCLUSIONS
The data confirm the importance of PGE2 in spinal nociceptive processing. The results suggest that antinociception after acetaminophen administration is mediated, at least in part, by inhibition of spinal PGE2 release. The mechanism, however, remains unknown. The finding that urinary excretion of prostaglandins was not affected might explain why acetaminophen is antinociceptive but does not compromise renal safety.
Muth-Selbach
U S
US
Department of Experimental and Clinical Pharmacology, University of Erlangen-Nürnberg, Erlangen, Germany. ums@macpost.pharmakologie.uni-erlangen.de
Tegeder
I
I
Brune
K
K
Geisslinger
G
G
D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D015232:Dinoprostone / Q000378:metabolism*; D008297:Male; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D015232:Dinoprostone