Non-steroidal anti-inflammatory drugs (NSAIDs) are thought to exert their pharmacological actions by a common mechanism: inhibition of cyclooxygenase (COX)-mediated prostanoid synthesis. Yet, differences and dissociation between their analgesic and anti-inflammatory effects have not been related to this enzymatic mechanism but mainly to pharmacokinetic factors. Thus, we have compared the effects of an equieffective anti-inflammatory dose (6 mg/kg i.p.) of two NSAIDs with comparable spinal pharmacokinetics, ketoprofen (moderately preferential for COX-1) and parecoxib (selective COX-2), on the activation of spinal nociceptive neurons (measured as c-Fos expression) induced by carrageenan-induced acute inflammation in the rat paw. Both NSAIDs showed a similar anti-inflammatory effect when administered after carrageenan injection (post-treatment). Post-treatment with ketoprofen produced inhibition of c-Fos but parecoxib did not have any significant effect. In addition, parecoxib anti-inflammatory effect was greater than that of ketoprofen, when administered before carrageenan injection (pre-treatment). Paradoxically, pre-treatment with ketoprofen produced a greater inhibition of c-Fos expression than with parecoxib, in all lamina of ipsilateral dorsal horn of the lumbar spinal cord. This suggests that NSAIDs therapeutic profile is related to their selectivity for COX isoforms and COX-2 is involved in the initiation but not in the maintenance of nociceptive spinal activation, which depends on COX-1.