Myricetin reduces voltage activated potassium channel currents in DRG neurons by a p38 dependent mechanism.

Myricetin is a naturally occurring flavonoid known for its anti-neoplastic, anti-oxidant and anti-inflammatory effects. Currently, potential analgesic effects are proposed for several animal models of acute and chronic pain. Pilot studies show a flavonoid-induced modulation of intracellular mitogen-activated protein kinases (MAPK) as p38 and interactions with voltage activated potassium channel currents (I(K(V))). The aim of this study was to investigate the underlying modulation of I(K(V)) and the influence of MAPK phosphorylation in an in vitro cell model. Whole cell patch-clamp recordings of rat dorsal root ganglion neurons were performed and I(K(V)) isolated. I(K(V)) were concentration-dependently reduced by myricetin (1-75µM myricetin; reduction range 18-78%) with no voltage dependency (-80 to +60mV). The reduction of I(K(V)) was enhanced by blocking p38 with the p38 inhibitor SB203580 (40±20% without SB203580 vs. 62±5% with 5µM SB203580 or 83±7% with 10µM SB203580), but abolished by activation of p38 using anisomycin (40±20% without anisomycin vs. 0.73±17% with 5µM anisomycin). We conclude that myricetin reduces I(K(V)) by p38 dependent mechanisms in sensory neurons. Since a reduction of I(K(V)) rather increases neuronal excitability, it is unlikely that this effect of myricetin contributes to its analgesic effects.

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 µM) concentrations of myricetin. This decrease was abolished by blockade of PKC (20 µM chelerythrine for 30 min), but not of p38 (10 µM SB203580 for 30 min). In contrast, higher (10-100 µM) 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.