NCX 2057, a novel NO‐releasing derivative of ferulic acid, suppresses inflammatory and nociceptive responses in in vitro and in vivo models

Background and purpose: We previously reported that NCX 2057, a compound comprising a nitric oxide (NO)‐releasing moiety and the natural antioxidant, ferulic acid (FA), inhibits pro‐inflammatory mediators through NO‐mediated gene regulation. Here, we have assessed the activities of NCX 2057 in models of inflammatory and neuropathic pain, and characterized its effects on cyclooxygenase (COX)‐1 and COX‐2. Experimental approach: Anti‐nociceptive and anti‐inflammatory activities of NCX 2057 were measured in vitro and in vivo in models of inflammatory (carrageenan) and neuropathic (chronic constriction injury; CCI) pain. Effects of NCX 2057 were measured on COX‐1 and COX‐2 activities in RAW 264.7 macrophages. Key results: NCX 2057 dose‐dependently inhibited single motor unit responses to noxious mechanical stimulation (ID50= 100 µmol·kg−1) and wind‐up responses in rats with paw inflammation induced by carrageenan. Moreover, NCX 2057 inhibited allodynic responses following CCI of the sciatic nerve [ipsilateral Paw Withdrawal Threshold (g): vehicle: 41.4 ± 3.3; NCX 2057: 76.3 ± 4.8 FA: 37.9 ± 15.5 at 175 µmol·kg−1]. NCX 2057 reversed carrageenan‐induced hyperalgesic responses in mice and inhibited prostaglandin E2 formation in paw exudates. Finally, NCX 2057 competitively inhibited COX‐1 and COX‐2 activities in whole RAW macophages (IC50= 14.7 ± 7.4 and 21.6 ± 7.5 µM, respectively). None of these properties were exhibited by equivalent treatments with FA or standard NO donor compounds. Conclusions and implications: These studies indicate that NCX 2057 is effective in chronic inflammatory and neuropathic pain models, probably because of its particular combination of anti‐COX, antioxidant and NO‐releasing properties.