Analysis of the mechanisms underlying the antinociceptive effect of epicatechin in diabetic rats

Aims The purpose of this study was to investigate the antinociceptive effect of epicatechin as well as the possible mechanisms of action in diabetic rats. Main methods Rats were injected with streptozotocin to produce hyperglycemia. The formalin test was used to assess the nociceptive activity. Key findings Acute pre-treatment with epicatechin (0.03-30 mg/kg, i.p.) prevented formalin-induced nociception in diabetic rats. Furthermore, daily or every other day treatment for 2 weeks with epicatechin (0.03-30 mg/kg, i.p.) also prevented formalin-induced nociception in diabetic rats. Acute epicatechin-induced antinociception was prevented by l-NAME (N ^ω-nitro-l-arginine methyl ester hydrochloride, 1-10 mg/kg, non-selective nitric oxide synthesis inhibitor), 7-nitroindazole (0.1-1 mg/kg, selective neuronal nitric oxide synthesis inhibitor), ODQ (1H-(1,2,4)- oxadiazolo(4,2-a)quinoxalin-1-one, 0.2-2 mg/kg, guanylyl cyclase inhibitor) or glibenclamide (1-10 mg/kg, ATP-sensitive K⁺ channel blocker). Moreover, epicatechin (3 mg/kg)-induced antinociception was fully prevented by methiothepin (0.1-1 mg/kg, serotonergic receptor antagonist), WAY-100635 (0.03-0.3 mg/kg, selective 5-HT_1A receptor antagonist) or SB-224289 (0.03-0.3 mg/kg, selective 5-HT_1B receptor antagonist). In contrast, BRL-15572 (0.03-0.3 mg/kg, selective 5-HT_1D receptor antagonist) only slightly prevented the antinociceptive effect of epicatechin. Naloxone (0.1-1 mg/kg, opioid antagonist) did not modify epicatechin's effect. Significance Data suggest the involvement of the nitric oxide-cyclic GMP-K⁺ channel pathway as well as activation of 5-HT_1A and 5HT_1B, and at a lesser extent, 5-HT_1D, but not opioid, receptors in the antinociceptive effect of epicatechin in diabetic rats. Our data suggest that acute or chronic treatment with epicatechin may prove to be effective to treat nociceptive hypersensitivity in diabetic patients.