Anti-allodynic effect of the flavonoid myricetin in a rat model of neuropathic pain: Involvement of p38 and protein kinase C mediated modulation of Ca2+ channels

Flavonoids are increasingly ingested by the population as chemotherapeutic and anti-inflammatory agents. Myricetin is a naturally occurring flavonoid known for its anti-neoplastic and anti-inflammatory effects. Recently, behavioral studies indicate a potential analgesic effect in animal models of pain. Pilot studies suggest a flavonoid-induced modulation of intracellular protein kinases and interactions with voltage activated calcium channels. The aim of this study was to investigate the analgesic effect of myricetin in a neuropathic pain model (spinal nerve ligation, SNL) in rats. To identify potential mechanisms of action, in vitro whole cell patch-clamp recordings of isolated rat dorsal root ganglia (DRG) neurons were performed to analyze the modulation of voltage activated calcium channel currents (I-Ca(V)) and the influence of intracellular kinase phosphorylation such as p38 mitogen-activated protein kinase (p38) or protein kinase C (PKC). In vivo, a single injection of myricetin (0.1-10 mg/kg i.p.) reduced SNL-induced mechanical allodynia and thermal hyperalgesia lasting for several hours. In vitro, I-Ca(V) (depolarization from -80 to 0 mV) were reduced (10-56%) by low (0.1-5 mu M) concentrations of myricetin. This decrease was abolished by blockade of PKC (20 mu M chelerythrine for 30 min), but not of p38 (10 mu M SB203580 for 30 min). In contrast, higher (10-100 mu M) concentrations of myricetin induced an increase of I-Ca(V) (20-40%), which was blocked by inhibition of p38, but not of PKC. We conclude that myricetin transiently reduces established neuropathic pain behavior. This analgesic effect may be related to its PKC-induced decrease of I-Ca(V) in DRG neurons. (C) 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.