Acetaminophen inhibits spinal prostaglandin E2 release after peripheral noxious stimulation

Background: Prostaglandins play a pivotal role in spinal nociceptive processing. At therapeutic concentrations, acetaminophen is not a cyclooxygenase inhibitor. Thus, it is antinociceptive without having antiinflammatory or gastrointestinal toxic effects. This study evaluated the role of spinal prostaglandin E-2 (PGE(2)) in antinociception produced by intraperitoneally administered acetaminophen. Methods: The PGE(2) 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 PGE(2) levels and flinching behavior was monitored. Spinal PGE(2) 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 PGE(2) 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 45-60 min after intraperitoneal administration. Urinary excretion of prostanoids (PGE(2), PGF(2 alpha), and 6-keto-PGF(1 alpha)) was not significantly altered after acetaminophen administration. Conclusions: The data confirm the importance of PGE(2) in spinal nociceptive processing. The results suggest that antinociception after acetaminophen administration is mediated, at least in part, by inhibition of spinal PGE(2) 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.