Antinociceptive effect of Dual Soluble Epoxide Hydrolase (sEH)/Fatty Acid Amide Hydrolase (FAAH) Inhibitors on TMJ hypernociception

Objectives: Soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) are two eicosanoid-regulating enzymes that have multiple overlapping physiologic roles. In particular, sEH and FAAH hydrolyze the analgesic mediators epoxyeicosatrienoic acid and arachidonoyl ethanolamide, respectively. Concurrent inhibition of sEH and FAAH resulting in synergistic efficacy in multiple pain models; thus, we have recently sought to design dual sEH/FAAH inhibitors called C-14, as tools to explore the biological mechanisms and applications of this synergy. Here, we report a new series of dual sEH/FAAH inhibitors that were designed around two pharmacophores: 3’-carbamoyl-[1,1’-biphenyl]-3-yl carbamates based on URB597 and 4-trifluoromethoxyphenyl ureas (TPPU) on temporomandibular joint hypernociception model.
Methods: Rats were pretreated (15 min) with an intra-TMJ injection of C-14, TPPU or URB597. After that, 1.5% formalin (15 µL/TMJ) was injected into TMJ. All animals received a final volume of 45 µL into TMJ. After TMJ injections, the nociceptive behavioral responses (sum of flinching and rubbing) were evaluated during 45-min observation period. To confirm theirs local effect, C-14, TPPU or URB597 were injected into the contralateral TMJ, and the 1.5% formalin was injected on the ipsilateral TMJ. Animals’ nociceptive behavior was observed during 45 minutes-period.
Results: The pretreatment (15 min before) with C-14 (100 and 300, but not 30 ng/TMJ); TPPU (10 and 30, but not 3 ng/TMJ) or URB597 (30 and 100, but not 3 ng/TMJ) reduced the nociceptive responses induced by 1.5% formalin in the TMJ (p<0.05). The contralateral (ct) pretreatment (15 min before) with C-14 (100 ng/TMJ); TPPU (30 ng/TMJ) or URB597 (100 ng/TMJ) had no effect (p>0.05).
Conclusions: The C-14 compound showed similar results with the individuals compounds showing the dual effect.