title: Glycogen synthase kinase 3-specific inhibitor AR-A014418 decreases neuropathic pain in mice: evidence for the mechanisms of action.
abstract: The present study examined the antihyperalgesic effect of a specific inhibitor of Glycogen Synthase Kinase 3 (GSK3), AR-A014418, on the partial ligation of the sciatic nerve (PSNL), a neuropathic pain model in mice and investigated some mechanisms of action. AR-A014418 (0.01-1 mg/kg) administered by intraperitoneal route (i.p.) inhibited mechanical hyperalgesia. This action started 30 min after i.p. administration and remained significant up to 2 h. When administered daily for 5 days, AR-A014418 (0.3 mg/kg, i.p.) significantly reduced the mechanical hyperalgesia caused by PSNL. Intraperitoneal (i.p.) treatment with AR-A014418 (0.3 mg/kg) also significantly inhibited cold hyperalgesia induced by PSNL. Pre-administration of PCPA (100 mg/kg, i.p., inhibitor of serotonin synthesis) and AMPT (100 mg/kg, i.p., inhibitor of tyrosine hydroxylase), but not l-arginine (600 mg/kg, i.p., a nitric oxide precursor), significantly reduced the mechanical hyperalgesia elicited by AR-A014418. Furthermore, the administration of AR-A014418 significantly prevented the increase of TNF-α (inhibition of 76±8%) and IL-1β (inhibition of 62±10%), but did not alter lumbar spinal cord IL1-ra and IL-10 levels. Finally, intraperitoneal administration of AR-A014418 did not affect locomotor activity in the open-field test. Taken together, these results provide experimental evidence indicating that AR-A014418 produces marked antihyperalgesic effects in neuropathic pain in mice, possibly due to mechanisms that reduce proinflammatory cytokines, as well as increases in serotonergic and catecholaminergic pathways. The present study suggests that GSK3 may be a novel pharmacological target for the treatment of neuropathic pain and AR-A014418 might be a potential molecule of interest for chronic pain relief.
authors.affiliation: Laboratório de Neurobiologia da Dor e Inflamação, Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário-Trindade, Florianópolis, SC, Brazil.
authors.forename: L
authors.initials: L
authors.lastname: Mazzardo-Martins
authors.forename: D F
authors.initials: DF
authors.lastname: Martins
authors.forename: J
authors.initials: J
authors.lastname: Stramosk
authors.forename: F J
authors.initials: FJ
authors.lastname: Cidral-Filho
authors.forename: A R S
authors.initials: AR
authors.lastname: Santos
mesh_terms: D000700:Analgesics; D000818:Animals; D001120:Arginine / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006930:Hyperalgesia / Q000188:drug therapy; D008026:Ligation; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009437:Neuralgia / Q000188:drug therapy*; D009569:Nitric Oxide / Q000502:physiology; D010147:Pain Measurement / Q000187:drug effects; D010275:Parasympathetic Nervous System / Q000502:physiology; D020426:Sciatic Neuropathy / Q000188:drug therapy; D012701:Serotonin / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000700:Analgesics; D016207:Cytokines; D004791:Enzyme Inhibitors; D013844:Thiazoles; D009569:Nitric Oxide; D012701:Serotonin; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D001120:Arginine; D038362:Glycogen Synthase Kinase 3