Antinociceptive properties of esculetin in non-inflammatory and inflammatory models of pain in rats

Some studies suggest that 5-lipoxygenase (5-LOX) inhibition or leukotriene receptor antagonism may effectively attenuate different kinds of pain. In the present study, we investigated whether esculetin (which, among other actions, potently inhibits 5-LOX) possesses analgesic activity in acute non-inflammatory pain and acute inflammatory pain models in rats. We also examined the effects of zileuton, a selective 5-LOX inhibitor, on esculetin activity. Plasma concentrations of leukotriene B-4 (LTB4) after administration of esculetin were also determined. Esculetin (1.25-20mg/kg, i.p.) dose-dependently alleviated hyperalgesia and exhibited antinociceptive effects in both experimental models. The greatest effect of esculetin was observed with a dose of 20mg/kg. In carrageenan-induced inflammatory pain in rats, 20mg/kg esculetin reversed or mitigated hyperalgesia, increasing the threshold to mechanical stimuli from a control value of -23.8 +/- 1.8% to 15.2 +/- 2.2% (P<0.01) and that to thermal stimuli from -52.5 +/- 6.1% to -9.5 +/- 3.9% (P<0.01). In non-inflammatory pain, after esculetin (20mg/kg) administration the threshold values to mechanical and thermal stimuli increased to 75.9 +/- 4.2% and 59.2 +/- 4.3%, respectively (P<0.01 for both). Zileuton (30mg/kg, p.o.) alone slightly but significantly increased the pain threshold in the non-inflammatory and inflammatory acute pain models. Pretreatment with 30mg/kg, p.o., zileuton significantly enhanced the analgesic activity of 5mg/kg, i.p., esculetin in both pain models. Moreover, esculetin (10mg/kg, i.p.) decreased LTB4 concentrations in the blood from 244 +/- 29pg/mL in the control group to 185 +/- 11pg/mL (P<0.005). The results of the present study suggest the involvement of the 5-LOX pathway in esculetin analgesia.