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

Tim Hagenacker, Imke Hillebrand, Andreas Wissmann, Dietrich Busselberg, Maria Schäfers

Research output: Contribution to journalArticle

27 Citations (Scopus)

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 (ICa(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, ICa(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 ICa(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 ICa(V) in DRG neurons.

Original languageEnglish
Pages (from-to)992-998
Number of pages7
JournalEuropean Journal of Pain
Volume14
Issue number10
DOIs
Publication statusPublished - Nov 2010

Fingerprint

Neuralgia
p38 Mitogen-Activated Protein Kinases
Flavonoids
Protein Kinase C
Hyperalgesia
Analgesics
Spinal Nerves
Spinal Ganglia
Calcium Channels
Ligation
Anti-Inflammatory Agents
Neurons
Mitogen-Activated Protein Kinase Kinases
Protein Kinases
Action Potentials
myricetin
Phosphotransferases
Animal Models
Phosphorylation
Pain

Keywords

  • Flavonoids
  • Myricetin
  • Neuropathic pain
  • Patch-clamp
  • Voltage activated calcium channel currents

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

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. / Hagenacker, Tim; Hillebrand, Imke; Wissmann, Andreas; Busselberg, Dietrich; Schäfers, Maria.

In: European Journal of Pain, Vol. 14, No. 10, 11.2010, p. 992-998.

Research output: Contribution to journalArticle

@article{244d66dd940241eab0b1687cf0de3e51,
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 (ICa(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, ICa(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 ICa(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 ICa(V) in DRG neurons.",
keywords = "Flavonoids, Myricetin, Neuropathic pain, Patch-clamp, Voltage activated calcium channel currents",
author = "Tim Hagenacker and Imke Hillebrand and Andreas Wissmann and Dietrich Busselberg and Maria Sch{\"a}fers",
year = "2010",
month = "11",
doi = "10.1016/j.ejpain.2010.04.005",
language = "English",
volume = "14",
pages = "992--998",
journal = "European Journal of Pain",
issn = "1090-3801",
publisher = "W.B. Saunders Ltd",
number = "10",

}

TY - JOUR

T1 - Anti-allodynic effect of the flavonoid myricetin in a rat model of neuropathic pain

T2 - Involvement of p38 and protein kinase C mediated modulation of Ca2+ channels

AU - Hagenacker, Tim

AU - Hillebrand, Imke

AU - Wissmann, Andreas

AU - Busselberg, Dietrich

AU - Schäfers, Maria

PY - 2010/11

Y1 - 2010/11

N2 - 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 (ICa(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, ICa(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 ICa(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 ICa(V) in DRG neurons.

AB - 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 (ICa(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, ICa(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 ICa(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 ICa(V) in DRG neurons.

KW - Flavonoids

KW - Myricetin

KW - Neuropathic pain

KW - Patch-clamp

KW - Voltage activated calcium channel currents

UR - http://www.scopus.com/inward/record.url?scp=78349305945&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78349305945&partnerID=8YFLogxK

U2 - 10.1016/j.ejpain.2010.04.005

DO - 10.1016/j.ejpain.2010.04.005

M3 - Article

VL - 14

SP - 992

EP - 998

JO - European Journal of Pain

JF - European Journal of Pain

SN - 1090-3801

IS - 10

ER -