Xu Hao, Xu Tao, Ma Xiaqing, Jiang Wei
Department of Anesthesiology, Shanghai Jiaotong University Affiliated Shanghai Sixth People's Hospital, Shanghai, China.
Br J Pharmacol. 2015 Jun;172(11):2892-904. doi: 10.1111/bph.13094. Epub 2015 Mar 24.
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.
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.
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.
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.
吗啡及其他阿片类药物诱导的耐受性仍是疼痛临床管理中一个主要未解决的问题。目前有充分证据表明丝裂原活化蛋白激酶（MAPKs）在吗啡诱导的抗伤害感受性耐受中具有重要作用。MAPK激酶激酶家族成员之一，转化生长因子-β激活激酶1（TAK1）是MAPKs的共同上游激酶。在此，我们评估了TAK1在吗啡诱导镇痛耐受性形成中的作用。
使用兰德尔-塞利托试验在体内研究TAK1拮抗剂对吗啡耐受性的影响，并使用蛋白质免疫印迹法和免疫组织化学法研究其机制。还通过免疫组织化学法在体外评估慢性吗啡暴露后TAK1的表达。
慢性鞘内注射吗啡可上调脊髓TAK1的蛋白水平和磷酸化水平。TAK1免疫反应性与神经元标志物NeuN共定位。鞘内注射选择性TAK1抑制剂5Z-7-氧代玉米烯醇（OZ）可减弱吗啡镇痛效力的丧失及吗啡诱导的TAK1上调。此外，OZ可降低重复给予吗啡后脊髓p38和JNK的上调表达。体外研究表明，持续给予吗啡可诱导TAK1上调，而联合给予OZ可使其逆转。一次性注射OZ可部分逆转已建立的吗啡抗伤害感受性耐受。
TAK1在吗啡诱导的抗伤害感受性耐受形成中起关键作用。在腰段脊髓中通过选择性抑制剂OZ调节TAK1的激活可能是一种有吸引力的辅助治疗方法，可减轻这种耐受性。
