Additive Antinociceptive Effects of the Selective Nav1.8 Blocker A-803467 and Selective TRPV1 Antagonists in Rat Inflammatory and Neuropathic Pain Models.

Abstract: Evidence implicating Nav1.8 and TRPV1 ion channels in various chronic pain states is extensive. In this study, we used isobolographic analysis to examine the in vivo effects of the combination of the Nav1.8 blocker A-803467 [5-(4-Chloro-phenyl)-furan-2-carboxylic acid (3,5-dimethoxy-phenyl)-amide] with 2 structurally distinct TRPV1 antagonists, A-840257 [1-(1H-Indazol-4-yl)-3-([R]-4-piperidin-1-yl-indan-1-yl)-urea] or A-425619 [1-Isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea]. The antinociceptive effects of the Nav1.8 blocker alone and in combination with each TRPV1 antagonist were examined in an inflammatory (complete Freund''s adjuvant, CFA) and a neuropathic (spinal nerve ligation, SNL) pain model after systemic (intraperitoneal) administration. Alone, A-803467 was efficacious in both CFA and SNL models with ED₅₀ values of 70 (54.2 to 95.8) mg/kg and 70 (38.1 to 111.9) mg/kg, respectively. The ED₅₀ values of the TRPV1 antagonists A-840257 and A-425619 alone in the CFA model were 10 (3.6 to 14.9) mg/kg and 43 (24.1 to 62.2) mg/kg, respectively; both were without significant effect in the SNL model. A series of experiments incorporating 1:1, 3:1, or 0.3:1 ED₅₀ dose-ratio combinations of A-840257 and A-803467, or A-425619 and A-803467 were performed in both pain models, and the effective doses of mixtures that produced 50% antinociception (ED_{50, mix}) were determined by isobolographic analysis. The ED_{50, mix} in each case was not found to be statistically different than ED_{50, add}, the theoretical ED₅₀ calculated assuming additive effects. These data demonstrate that Nav1.8 blockers and TRPV1 antagonists administered in combination produce an additive effect in rat pain models. Using such a combination strategy to produce analgesia may potentially provide an improved therapeutic separation from unwanted in vivo side effects associated with blockade of either Nav1.8 or TRPV1 alone. Perspective: In this report, effects of coadministration of TRPV1 antagonists and A-803467, a Nav1.8 blocker, were investigated in preclinical rodent models of neuropathic and inflammatory pain. The 2 classes of novel antinociceptive agents produced an additive interaction in attenuating CFA-induced thermal hyperalgesia, providing a rationale for their use as a combination strategy in the clinic for treating inflammatory pain. [Copyright &y& Elsevier]