NCX-701 (nitroparacetamol) is a NO-releasing derivative of paracetamol (acetaminophen) that has shown potent antinociceptive and anti-inflammatory properties (Romero-Sandoval et al. 2002). We have compared the antinociceptive activity of I.V. NCX-701 vs. paracetamol in single motor unit recordings (SMU) from monoarthritic male Wistar rats. NCX-701 was also tested in sham and full-spinalized animals to assess whether or not the effect was located at spinal cord sites. Monoarthritis was induced by the administration of 50 µl of carrageenan in the knee cavity under brief halothane anaesthesia 16 h previous to the experiment. Preparatory surgery was also made under halothane anaesthesia and included the cannulation of the trachea, two superficial branches of the jugular veins, and one carotid artery. Spinalization or sham operation was performed at the vertebral T9-10 segment. SMU recordings were performed in hind limb muscles by means of bipolar tungsten electrodes under systemic chloralose anaesthesia. The animals were humanly killed at the end of the experiment by an overdose of pentobarbitone.

In normal animals, the administration of cumulative doses of NCX-701 induced a dose-dependent reduction of responses to noxious mechanical stimulation, similar to that seen with paracetamol (ID₅₀ values of 320 and 305 µmol kg^-1, respectively, n = 9). The maximum effect observed was of 30 % of control response for paracetamol and 22 % for NCX-701. SMU wind-up, however, was significantly (P < 0.05, ANOVA with Dunnett’s post hoc test) reduced by NCX-701 but not modified by paracetamol, indicating a different mechanism of action. In spinalized animals, NCX-701 reduced responses to mechanical and electrical stimulation with a similar potency to that seen in normal non-spinalized animals (ID₅₀ of 327 µmol kg^-1, n = 8). In sham-spinalized animals, however, the effect of NCX-701 on responses to noxious mechanical stimulation was very week and not dose dependent, with a maximum effect of 58 % of control response. Also, wind-up responses remained unchanged in sham spinalized rats.

We conclude that NCX-701 induces a potent antinociceptive effect by a mechanism different from and complementary to that of paracetamol, and its action is mainly located within the spinal cord in monoarthritic animals.

This work was supported by NicOx S.A. and Spanish Ministry of Education, SAF2001-1048-C03-03.