Sustained morphine treatment augments basal CGRP release from cultured primary sensory neurons in a Raf-1 dependent manner
Sustained morphine treatment augments basal CGRP release from cultured primary sensory neurons in a Raf-1 dependent manner
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DOI：
10.1016/j.ejphar.2008.02.013
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发表时间：
2008-04-28
影响因子：
5
通讯作者：
Varga, Eva V.
中科院分区：
文献类型：
--
作者：
Yue, Xu;Tumati, Suneeta;Varga, Eva V.
最近的研究表明，持续吗啡介导的悖论性疼痛可能在镇痛耐受的发展中起重要作用。参与持续阿片介导的脊髓疼痛神经递质（如降钙素基因相关肽（CGRP））释放增加的细胞内信号转导通路尚不完全清楚。环AMP （cAMP）依赖性蛋白激酶（PKA）在突触前神经递质释放的调节中起重要作用。此外，我们之前已经表明，持续的阿片受体激动剂治疗导致raf -1依赖性腺苷酸环化酶增敏（AC超激活），增加阿片戒断时福斯克林刺激的cAMP形成（cAMP超调）。因此，在本研究中，我们在体外培养的新生大鼠背根神经节（DRG）神经元中检测了Raf-1在吗啡介导的cAMP的持续调节和CGRP的基础释放中的作用。我们发现，持续的吗啡治疗显著增加了培养的新生大鼠DRG神经元细胞内cAMP的产生和基础CGRP的释放。选择性PKA抑制剂H-89可减弱吗啡介导的CGRP基础释放的持续增加，表明cAMP/PKA通路在调节感觉神经元CGRP释放中起重要作用。由于我们目前的数据还表明，选择性Raf-1抑制剂GW 5074可以减轻新生儿大鼠DRG神经元中持续吗啡介导的cAMP过调和CGRP释放的增加，我们认为Raf-1介导的细胞内cAMP形成的增敏可能在持续吗啡介导的脊髓疼痛神经递质释放的增加中发挥重要作用。(c) 2008 Elsevier B.V.版权所有
Recent studies suggest that sustained morphine-mediated paradoxical pain may play an important role in the development of analgesic tolerance. The intracellular signal transduction pathways involved in sustained opioid mediated augmentation of spinal pain neurotransmitter (such as calcitonin gene-related peptide (CGRP)) release are not fully clarified. Cyclic AMP (cAMP)-dependent protein kinase (PKA) plays an important role in the modulation of presynaptic neurotransmitter release. Moreover, we have shown earlier that sustained opioid agonist treatment leads to a Raf-1-dependent sensitization of adenylyl cyclase(s) (AC superactivation), augmenting forskolin-stimulated cAMP formation upon opioid withdrawal (cAMP overshoot). Therefore, in the present study we examined the role of Raf-1 in sustained morphine-mediated regulation of cAMP fort-nation and basal CGRP release in vitro, in cultured neonatal rat dorsal root ganglion (DRG) neurons. We found that sustained morphine treatment significantly augments intracellular cAMP production as well as basal CGRP release from cultured neonatal rat DRG neurons. The selective PKA inhibitor, H-89, attenuates the sustained morphine-mediated augmentation of basal CGRP release, indicating that the cAMP/PKA pathway plays an important role in regulation of CGRP release from sensory neurons. Since our present data also demonstrated that selective Raf-1 inhibitor, GW 5074, attenuated both the cAMP overshoot and the augmentation of CGRP release mediated by sustained morphine in neonatal rat DRG neurons, we suggest that Raf-1-mediated sensitization of the intracellular cAMP formation may play an important role in sustained morphine-mediated augmentation of spinal pain neurotransmitter release. (c) 2008 Elsevier B.V. All rights reserved.