The antinociceptive effects of AR-A014418, a selective inhibitor of glycogen synthase kinase-3 beta, in mice

J Pain. 2011 Mar;12(3):315-22. doi: 10.1016/j.jpain.2010.06.007. Epub 2010 Aug 12.

Abstract

We investigated the antinociceptive effects of AR-A014418, a selective inhibitor of glycogen synthase kinase-3β (GSK-3β) in mice. A 30-minute pretreatment with AR-A014418 (.1 and 1 mg/kg, intraperitoneal [ip]) inhibited nociception induced by an ip injection of acetic acid. AR-A014418 pretreatment (.1 and .3 mg/kg, ip) also decreased the late (inflammatory) phase of formalin-induced licking, without affecting responses of the first (neurogenic) phase. In a different set of experiments, AR-A014418 (.1-10 μg/site) coinjected intraplantarly (ipl) with formalin inhibited the late phase of formalin-induced nociception. Furthermore, AR-A014418 administration (1 and 10 ng/site, intrathecal [it]) inhibited both phases of formalin-induced licking. In addition, AR-A014418 coinjection (10 ng/site, it) inhibited nociception induced by glutamate, N-methyl-D-aspartate (NMDA), (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β) by 47 ± 12%, 48 ± 11%, 31 ± 8%, 46 ± 13%, and 44 ± 11%, respectively. In addition, a 30-minute pretreatment with NP031115 (3 and 10 mg/kg, ip), a different GSK-3 β inhibitor, also attenuated the late phase of formalin-induced nociception. Collectively, these results provide convincing evidence that AR-A014418, given by local, systemic, and central routes, produces antinociception in several mouse models of nociception. The AR-A014418-dependent antinociceptive effects were induced by modulation of the glutamatergic system through metabotropic and ionotropic (NMDA) receptors and the inhibition of the cytokine (TNF-α and IL-1β) signaling.

Perspective: These results suggest that GSK-3β may be a novel pharmacological target for the treatment of pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abdominal Pain / chemically induced
  • Abdominal Pain / prevention & control*
  • Aggression / drug effects
  • Analgesics / administration & dosage*
  • Analysis of Variance
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal
  • Azides / administration & dosage
  • Cytokines / administration & dosage
  • Cytokines / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Administration Routes
  • Formaldehyde / adverse effects
  • Glutamic Acid / adverse effects
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Inflammation / chemically induced
  • Inflammation / drug therapy
  • Male
  • Mice
  • N-Methylaspartate / administration & dosage
  • Pain Measurement / methods
  • Sugar Acids / adverse effects
  • Thiazoles / administration & dosage*
  • Urea / administration & dosage
  • Urea / analogs & derivatives*
  • Xylose / adverse effects
  • Xylose / analogs & derivatives

Substances

  • 3-C-carboxy-5-deoxyxylose
  • Analgesics
  • Anti-Inflammatory Agents, Non-Steroidal
  • Azides
  • Cytokines
  • Sugar Acids
  • Thiazoles
  • N-(3-iodo-4-azidophenylpropionamido)-S-(2-thiopyridyl)cysteine
  • Formaldehyde
  • Glutamic Acid
  • N-Methylaspartate
  • N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
  • Urea
  • Xylose
  • Glycogen Synthase Kinase 3