Ca2+/calmodulin-dependent protein kinase II alpha is required for the initiation and maintenance of opioid-induced hyperalgesia.
Ca2+/calmodulin-dependent protein kinase II alpha is required for the initiation and maintenance of opioid-induced hyperalgesia.
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DOI：
10.1523/jneurosci.4346-09.2010
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发表时间：
2010-01-06
期刊：
影响因子：
--
通讯作者：
Wang ZJ
中科院分区：
文献类型：
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作者：
Chen Y;Yang C;Wang ZJ
阿片类药物的重复给药不仅导致耐受性和依赖性，而且导致伤害性增强，称为阿片类药物诱导的痛觉过敏（OIH）。参与OIH生成的伤害性介质仍然知之甚少。在本研究中，我们验证了Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKIIα）在OIH中至关重要的假设。阿片类药物诱导的痛觉过敏是通过重复给药吗啡或颗粒植入小鼠。与触觉异常性疼痛和热痛觉过敏的发展相关，OIH时脊髓CaMK Ⅱ α活性显著增加。KN 93，一种CaMKII抑制剂，剂量和时间依赖性逆转OIH和CaMKII激活，而不损害运动协调。为了阐明所涉及的特异性CaMKII亚型，我们采用小干扰RNA靶向CaMKIIα，并证明敲低脊髓CaMKIIα可减弱OIH。此外，吗啡不能诱导CaMKIIα T286 A点突变小鼠的OIH，尽管野生型同窝小鼠在用吗啡重复处理后发生了强烈的OIH。这些数据首次表明CaMKIIα作为导致和维持阿片类药物诱导的痛觉过敏的细胞机制的重要作用。
Repeated administration of opioids not only leads to tolerance and dependence, but also results in nociceptive enhancement called opioid-induced hyperalgesia (OIH). Nociceptive mediators involved in OIH generation remain poorly understood. In the present study, we tested the hypothesis that Ca2+/calmodulin-depent protein kinase II (CaMKIIα) is critical for OIH. Opioid-induced hyperalgesia was produced by repeated morphine administration or pellet implantation in mice. Correlating with the development of tactile allodynia and thermal hyperalgesia, spinal CaMKIIα activity was significantly increased in OIH. KN93, a CaMKII inhibitor, dose- and time-dependently reversed OIH and CaMKII activation without impairing locomotor coordination. To elucidate the specific CaMKII isoform involved, we targeted CaMKIIα by employing small interfering RNA and demonstrated that knockdown of spinal CaMKIIα attenuated OIH. Furthermore, morphine failed to induce OIH in CaMKIIαT286A point mutant mice, although wild-type littermate mice developed robust OIH after repeated treatments with morphine. These data implicate, for the first time, an essential role of CaMKIIα as a cellular mechanism leading to and maintaining opioid-induced hyperalgesia.