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


CONCLUSIONS
These results suggest that GSK-3β may be a novel pharmacological target for the treatment of pain.
Martins
Daniel F
DF
Departamento de Ciências Fisiológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
Rosa
Angelo O
AO
Gadotti
Vinícius M
VM
Mazzardo-Martins
Leidiane
L
Nascimento
Francisney P
FP
Egea
Javier
J
López
Manuela G
MG
Santos
Adair R S
AR
D015746:Abdominal Pain / Q000139:chemically induced / Q000517:prevention & control*; D000374:Aggression / Q000187:drug effects; D000700:Analgesics / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001386:Azides / Q000008:administration & dosage; D016207:Cytokines / Q000008:administration & dosage / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D005557:Formaldehyde / Q000009:adverse effects; D018698:Glutamic Acid / Q000009:adverse effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000008:administration & dosage; D010147:Pain Measurement / Q000379:methods; D013400:Sugar Acids / Q000009:adverse effects; D013844:Thiazoles / Q000008:administration & dosage*; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014994:Xylose / Q000009:adverse effects / Q000031:analogs & derivatives
C511260:3-C-carboxy-5-deoxyxylose; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001386:Azides; D016207:Cytokines; D013400:Sugar Acids; D013844:Thiazoles; C057771:N-(3-iodo-4-azidophenylpropionamido)-S-(2-thiopyridyl)cysteine; D005557:Formaldehyde; D018698:Glutamic Acid; D016202:N-Methylaspartate; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D014994:Xylose; D038362:Glycogen Synthase Kinase 3