Antinociceptive effects of NCX-701 (nitro-paracetamol) in neuropathic rats: enhancement of antinociception by co-administration with gabapentin

Abstract

Background and purpose: Neuropathic pain is characterized by a poor response to classic analgesics. In the present study, we have assessed the antinociceptive activity of NCX-701 (nitro-paracetamol) in neuropathic rats, after systemic and intrathecal (i.t.) administration. In addition, we analysed the possible benefit of the combination of NCX-701 and gabapentin, a well-known potent analgesic, in the treatment of neuropathic pain.

Experimental approach: The antinociceptive effects of i.v. and i.t. NCX-701 and paracetamol were studied in spinal cord neuronal responses from neuropathic adult male Wistar rats, using the recording of single motor units technique. The effect of i.v. and i.t. NCX-701 in combination with i.v. gabapentin was studied by isobolographic analysis.

Key results: The experiments showed that NCX-701, but not paracetamol, dose-dependently reduced the nociceptive responses evoked by noxious mechanical and electrical stimulation, after i.v. (ID(50) 542 +/- 5 micromol kg(-1) for noxious mechanical stimulation) or i.t. (ID(50) 932 +/- 16 nmol kg(-1)) administration. The combined administration of i.v. or i.t. NCX-701 and i.v. gabapentin induced a more intense antinociceptive effect than any of the two drugs given alone. The isobolographic analysis showed a synergistic effect.

Conclusions and implications: NCX-701 is an effective antinociceptive compound in situations of neuropathy-induced sensitization, with an action mainly located in the spinal cord. The combination of NCX-701 and gabapentin induces a synergistic enhancement of the depression of nociceptive responses evoked by natural noxious stimulation. The use of NCX-701 alone or in combination with gabapentin might open up new and promising perspectives in the treatment of neuropathic pain.

Figure 1

Antinociceptive effect of i.v. (upper panel) and intrathecal (i.t.) (lower panel) NCX-701 and paracetamol on responses to noxious mechanical stimulation. The i.v. or i.t. administration of paracetamol did not reduce significantly the responses to noxious mechanical stimulation in neuropathic rats. However, the administration of NCX-701 reduced dose-dependently the responses with an ID₅₀ of 542 ± 5 µmol·kg⁻¹ after i.v. administration and an ID₅₀ of 932 ± 16 nmol·kg⁻¹ after i.t. administration. Statistical analysis was made with the one-way anova, with the post hoc Dunnett's test, comparing the effect of NCX-701 versus control response (*P < 0.05, **P < 0.01) and versus the effect of paracetamol (#P < 0.05, ##P < 0.01).

Figure 2

Effect of i.v. (upper panel) and intrathecal (i.t.) (lower panel) NCX-701 and paracetamol on wind-up. The administration of paracetamol only reduced the wind-up phenomenon with the highest dose studied after i.v. administration. No significant effect was observed after i.t. administration. NCX-701, however, induced a dose-dependent and almost complete inhibition of wind-up in neuropathic rats after i.v. administration (maximal reduction of 18 ± 7% of control response). The i.t. administration of NCX-701 also induced a dose-dependent reduction of wind-up in neuropathic rats (maximal reduction of 41 ± 11% of control response). The figure shows the effect of NCX-701 and paracetamol on wind-up as a percentage of control, and the effect of NCX-701 as the actual number of C-fibre-mediated responses (insets). Statistical comparison and layout as for Figure 1.

Figure 3

Antinociceptive effect of the combined i.v. administration of NCX-701 and gabapentin on responses to noxious mechanical stimulation. Top panel: the reduction of responses, evoked by noxious mechanical stimulation, observed after i.v. NCX-701 and i.v. gabapentin when given together and separately. The combined i.v. administration of NCX-701 and gabapentin induced a more intense antinociceptive effect than either of the two drugs alone. Lower panel: the isobolographic analysis, which showed that the experimental point lies far below the additive line, indicating a significant synergism. The calculated ID₅₀ was 72 ± 18 nmol·kg⁻¹, significantly different from the theoretical ID₅₀ (##P < 0.01, Student's t-test). The figure also shows the interaction index, well below 1. Statistical analysis of the antinociceptive effect was made with the one-way anova, with the post hoc Dunnett's test, comparing the effect of the drugs versus their own control responses (*P < 0.05, **P < 0.01).

Figure 4

Antinociceptive effect of the combined administration of intrathecal (i.t.) NCX-701 and i.v. gabapentin on responses to noxious mechanical stimulation. Top panel: the reduction of responses, evoked by noxious mechanical stimulation, observed after i.t. NCX-701 and i.v. gabapentin when given together and separately. Similar to that seen in experiments carried out with the systemic administration of the two drugs, the combined administration of i.t. NCX-701 and i.v. gabapentin induced a more intense antinociceptive effect than either of the two drugs given alone. Lower panel: the isobolographic analysis, which showed that the effect observed with the combination of the drugs was the result of a synergistic effect. The calculated ID₅₀ was 265 ± 42 nmol·kg⁻¹, significantly different from the theoretical ID₅₀ (##P < 0.01, Student's t-test). The interaction index, well below 1, is also shown. Statistical analysis of the antinociceptive effect was made with the one-way anova, with the post hoc Dunnett's test, comparing the effect of the drugs versus their own control responses (*P < 0.05, **P < 0.01).