Antinociceptive effect of (−)-epicatechin in inflammatory and neuropathic pain in rats
The aim of this study was to investigate the antinociceptive potential of (−)-epicatechin and the possible mechanisms of action involved in its antinociceptive effect. The carrageenan and formalin tests were used as inflammatory pain models. A plethysmometer was used to measure inflammation and L5/L6 spinal nerve ligation as a neuropathic pain model. Oral (−)-epicatechin reduced carrageenan-induced inflammation and nociception by about 59 and 73%, respectively, and reduced formalin- induced and nerve injury-induced nociception by about 86 and 43%, respectively. (−)-Epicatechin-induced antinociception in the formalin test was prevented by the intraperitoneal administration of antagonists: methiothepin (5-HT1/5 receptor), WAY-100635 (5-HT1A receptor), SB-224289 (5-HT1B receptor), BRL-15572 (5-HT1D receptor), SB-699551 (5-HT5A receptor), naloxone (opioid receptor), CTAP (μ opioid receptor), nor-binaltorphimine (κ opioid receptor), and 7-benzylidenenaltrexone (δ1 opioid receptor). The effect of (−)-epicatechin was also prevented by the intraperitoneal administration of L-NAME [nitric oxide (NO) synthase inhibitor], 7-nitroindazole (neuronal NO synthase inhibitor), ODQ (guanylyl cyclase inhibitor), glibenclamide (ATP-sensitive K+ channel blocker), 4-aminopyridine (voltage-dependent K+ channel blocker), and iberiotoxin (large-conductance Ca2+-activated K+ channel blocker), but not by amiloride (acid sensing ion channel blocker). The data suggest that (−)-epicatechin exerts its antinociceptive effects by activation of the NO-cyclic GMP-K+ channels pathway, 5-HT1A/1B/1D/5A serotonergic receptors, and μ/κ/δ opioid receptors.