Pharmacodynamics of soluble hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), and its synergistic interactions with tramadol and meloxicam in rat orofacial formalin test

Nowadays, many researchers have directed attention towards arachidonic acid (AA) metabolism and in particular, to the cytochrome P450 (CYP450) enzymes, which convert it to epoxyeicosatrienoic acids (EETs). EETs have been shown to produce anti-inflammatory, analgesic, and cardioprotective effects. However, EETs are unstable in vivo due to their rapid metabolism by soluble epoxide hydrolase (sEH). This study was aimed to evaluate the anti-nociceptive efficacy of soluble hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), and drug interaction with meloxicam and tramadol. Male Wistar rats aged 6-7 weeks and weighing (180-200 g) were used. The orofacial formalin test was used to evaluate anti-nociceptive effects of drugs. All drugs with increasing doses were given by oral gavage 30 min before administration of formalin. The degree of nociception was assessed as the area under the time course of response (face rubbing) curve. Anti-nociceptive effect of both phases was established based on the percentage of the maximum possible effect (%MPE). An isobolographic analysis was performed to evaluate the interaction between TPPU and analgesics (tramadol and meloxicam). After administration of drugs, nociception has been shown a dose-dependent reduction in face rubbing behavior. All drugs produced anti-nociceptive effects in a dose-dependent manner in both phases. TPPU was found to be more potent and effective than tramadol and meloxicam. Mean values of interaction index of TPPU with tramadol and meloxicam were 0.23 and 0.34, respectively. Co-administration of TPPU enhanced the anti-nociceptive effects of tramadol and meloxicam in rat orofacial formalin test. The results in this study indicate that potency of TPPU is higher than those of tramadol and meloxicam. Co-administration of TPPU with tramadol and meloxicam might be new option for the treatment of pain.