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The Antinociceptive Effects of AR-A014418, a Selective Inhibitor of Glycogen Synthase kinase-3 Beta, in Mice

The Antinociceptive Effects of AR-A014418, a Selective Inhibitor of Glycogen Synthase kinase-3 Beta, in Mice

Daniel F Martins, Angelo O Rosa, Vinícius M Gadotti, Leidiane Mazzardo-Martins, Francisney P Nascimento, Javier Egea, Manuela G López, Adair R S Santos

J Pain. 2011 Mar;12(3):315-22.

PMID: 20705523

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP487021523-A	AR-A014418		487021-52-3	Price

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