当前位置： SCI文献检索 > BRITISH JOURNAL OF PHARMACOLOGY期刊下所有文献 > Involvement of neuronal TGF-β activated kinase 1 in the development of tolerance to morphine-induced antinociception in rat spinal cord.

Involvement of neuronal TGF-β activated kinase 1 in the development of tolerance to morphine-induced antinociception in rat spinal cord.

Abstract：

BACKGROUND AND PURPOSE:Tolerance induced by morphine and other opiates remains a major unresolved problem in the clinical management of pain. There is now good evidence for the importance of MAPKs in morphine-induced antinociceptive tolerance. A member of the MAPK kinase kinase family, TGF-β activated kinase 1 (TAK1) is the common upstream kinase of MAPKs. Here, we have assessed the involvement of TAK1 in the development of tolerance to morphine-induced analgesia. EXPERIMENTAL APPROACH:The effects of an antagonist of TAK1 on morphine tolerance were investigated in vivo using the Randall-Selitto test, and the mechanism was investigated using Western blot and immunohistochemistry. The expression of TAK1 after chronic morphine exposure was also evaluated in vitro by immunohistochemistry. KEY RESULTS:Chronic intrathecal morphine exposure up-regulated protein levels and phosphorylation of spinal TAK1. TAK1 immunoreactivity was co-localized with the neuronal marker NeuN. Intrathecal administration of 5Z-7-oxozeaenol (OZ), a selective TAK1 inhibitor, attenuated the loss of morphine analgesic potency and morphine-induced TAK1 up-regulation. Furthermore, OZ decreased the up-regulated expression of spinal p38 and JNK after repeated morphine exposure. In vitro studies demonstrated that sustained morphine treatment induced TAK1 up-regulation, which was reversed by co-administration of OZ. A bolus injection of OZ showed some reversal of established morphine antinociceptive tolerance. CONCLUSIONS AND IMPLICATIONS:TAK1 played a pivotal role in the development of morphine-induced antinociceptive tolerance. Modulation of TAK1 activation by the selective inhibitor OZ in the lumbar spinal cord may prove to be an attractive adjuvant therapy to attenuate such tolerance.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Xu H,Xu T,Ma X,Jiang W

doi

10.1111/bph.13094

subject

Has Abstract

pub_date

2015-06-01 00:00:00

pages

2892-904

issue

eissn

0007-1188

issn

1476-5381

journal_volume

172

pub_type

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Involvement of neuronal TGF-β activated kinase 1 in the development of tolerance to morphine-induced antinociception in rat spinal cord.