The µ-opioid agonist fentanyl is a very effective analgesic drug, though its effect is very short. Subeffective doses of the NSAID dexketoprofen trometamol enhanced the effect of fentanyl in responses to noxious mechanical stimulation (Gaitan & Herrero, 2002). We have now studied the possible interaction between NCX-701 (NOP, nitroparacetamol), the NO-releasing derivative of paracetamol (acetaminophen), in comparison to that of dexketoprofen trometamol (DKT) in single motor units (SMU) activated by noxious mechanical stimulation and high intensity electrical stimulation (wind-up).

Preparatory surgery, in male Wistar rats under halothane anaesthesia included the cannulation of the trachea, two superficial jugular veins and one carotid artery. The experiments were performed under chloralose anaesthesia and the animals were humanly killed by an overdose of pentobarbitone. The I.V. administration of fentanyl induced a dose-dependent inhibition of pinch-evoked responses to noxious mechanical stimulation (ID₅₀: 18 µg kg^-1, n = 10) that fully recovered in 30 min. In the presence of 60 µmol kg^-1 of NOP, fentanyl caused an inhibition of responses with an ID₅₀ of 5.2 µg kg^-1 (n = 7). This enhancement of the potency of fentanyl was similar to that observed when studied in the presence of 0.1 µmol kg^-1 of DKT (ID50: 4.7 µg kg^-1, n = 7). In the presence of either NOP or DKT, no recovery of the effect of fentanyl was observed for at least 45 min, and was not reversed by the I.V. administration of the opioid antagonist naloxone (200 µg kg^-1) or the α₂-adrenoceptor antagonist atipamezol (100 µg kg^-1). SMU wind-up was reduced by fentanyl with a minimal effective dose (MED) of 32 µg kg^-1 and fully recovered in 15 min. In the presence of NOP, the fentanyl MED was of 16 µg kg^-1, and the effect was still significant 15 min later. In the presence of DKT, however, although the MED was lower (16 µg kg^-1) to that observed in the absence of DKT, the effect fully recovered 30 min after the administration of the highest dose of fentanyl.

In conclusion, the presence of subeffective doses of NCX-701 induces a potent enhancement of the potency and duration of the antinociceptive effect of the µ-opioid receptor agonist fentanyl, in responses to noxious mechanical stimulation. This effect seems to be independent on the presence of NO since a similar action was observed in the presence of DKT. In wind-up, however, the enhancement of the effect observed after the administration of fentanyl seems to be more dependent on the release of NO since the enhancement observed in the presence of DKT was not so evident.

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