当前位置： SCI文献检索 > NEUROSCIENCE期刊下所有文献 > Glycogen synthase kinase 3-specific inhibitor AR-A014418 decreases neuropathic pain in mice: evidence for the mechanisms of action.

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.

journal_name

Neuroscience

journal_title

Neuroscience

authors

Mazzardo-Martins L,Martins DF,Stramosk J,Cidral-Filho FJ,Santos AR

doi

10.1016/j.neuroscience.2012.09.020

subject

Has Abstract

pub_date

2012-12-13 00:00:00

pages

411-20

eissn

0306-4522

issn

1873-7544

pii

S0306-4522(12)00923-2

journal_volume

226

pub_type

杂志文章

在线工具

Glycogen synthase kinase 3-specific inhibitor AR-A014418 decreases neuropathic pain in mice: evidence for the mechanisms of action.