Comparison of the antinociceptive activity of two new NO‐releasing derivatives of the NSAID S‐ketoprofen in rats

Nonsteroidal anti‐inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes inducing analgesic, anti‐inflammatory and antipyretic actions. They are not devoid of severe side effects and so, the search for new compounds with similar or higher effectiveness and a lower incidence of undesired actions is important. Nitric oxide (NO)‐releasing NSAIDs resulted from this search. We have compared the antinociceptive effectiveness of cumulative doses of two new NO‐releasing derivatives of S‐ketoprofen, HCT‐2037 and HCT‐2040, using the recording of spinal cord nociceptive reflexes in anesthetized and awake rats and after intravenous and oral administration. S‐ketoprofen and HCT‐2040 were equieffective in reducing responses to noxious mechanical stimulation after i.v. administration in anesthetized animals (ID50s: 1.3±0.1 and 1.6±0.2 μmol kg−1 respectively), but did not modify wind‐up. HCT‐2037 was two‐fold more potent (ID50 of 0.75±0.1 μmol kg−1) in responses to mechanical stimuli and very effective in reducing wind‐up (63±17% of control; P