title: 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.
abstract: 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.
authors.affiliation: Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Hagenacker
authors.forename: Imke
authors.initials: I
authors.lastname: Hillebrand
authors.forename: Andreas
authors.initials: A
authors.lastname: Wissmann
authors.forename: Dietrich
authors.initials: D
authors.lastname: Büsselberg
authors.forename: Maria
authors.initials: M
authors.lastname: Schäfers
mesh_terms: D018712:Analgesics, Non-Narcotic; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015220:Calcium Channels / Q000378:metabolism*; D004594:Electrophysiology; D005419:Flavonoids / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology; D006358:Hot Temperature; D008026:Ligation; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D018408:Patch-Clamp Techniques; D010812:Physical Stimulation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013127:Spinal Nerves; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018712:Analgesics, Non-Narcotic; D015220:Calcium Channels; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; C040015:myricetin; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases