Niiyama Y, Kawamata T, Yamamoto J, Omote K, Namiki A
Department of Anesthesiology, Sapporo Medical University School of Medicine, South 1 West 16, Sapporo, Hokkaido 060-8543, Japan.
Neuroscience. 2007 Aug 24;148(2):560-72. doi: 10.1016/j.neuroscience.2007.05.049. Epub 2007 Jul 25.
Bone cancer pain has a strong impact on the quality of life of patients but is difficult to treat. Therefore, the mechanisms of bone cancer pain require elucidation for the purpose of development of new therapeutics. A recent study showed that activation of transient receptor potential vanilloid subfamily 1 (TRPV1) was involved in bone cancer pain. In this study, we re-evaluated the analgesic effects of pharmacological blockade of TRPV1 using the potent TRPV1 antagonist 5-iodoresiniferatoxin (I-RTX) and examined whether bone cancer can change TRPV1 expression and distribution in the primary sensory neurons in a mouse model of bone cancer pain. Implantation of osteosarcoma into the femur induced ongoing and movement-evoked bone cancer-related pain behaviors. These behaviors were significantly reduced by i.p. administration of I-RTX, compared with vehicle. Western blot and reverse transcription-polymerase chain reaction (RT-PCR) analyses revealed that TRPV1 level was significantly increased in dorsal root ganglions (DRGs) ipsilateral to sarcoma implantation. Immunohistochemical analysis showed that implantation of osteosarcoma induced not only an increase in the percentage of TRPV1-positive neurons among DRG neurons (24.3+/-1.3% in sham mice and 31.2+/-1.3% in mice with osteosarcoma implantation, P<0.05) but also an overall shift in the distribution of area of profiles to the right. Colocalization study showed that the percentages of colocalization of TRPV1 with neurofilament 200 kD (NF200) and calcitonin gene-related peptide (CGRP) but not isolectin B4 (IB4) among DRG neurons in mice with osteosarcoma implantation were increased compared with those in sham mice (from 0.8+/-0.1% to 2.1+/-0.3% for TRPV1 and NF200 and from 21.1+/-1.3% to 26.5+/-0.2% for TRPV1 and CGRP). In conclusion, TRPV1 activation plays a critical role in the generation of bone cancer pain, and bone cancer increases TRPV1 expression within distinct subpopulation of DRG neurons. These findings may lead to novel strategies for the treatment of bone cancer pain.
骨癌疼痛对患者的生活质量有很大影响，但难以治疗。因此，为了开发新的治疗方法，需要阐明骨癌疼痛的机制。最近的一项研究表明，瞬时受体电位香草酸亚家族1（TRPV1）的激活与骨癌疼痛有关。在本研究中，我们使用强效TRPV1拮抗剂5-碘树脂毒素（I-RTX）重新评估了TRPV1药理阻断的镇痛效果，并研究了骨癌是否会改变骨癌疼痛小鼠模型中初级感觉神经元中TRPV1的表达和分布。将骨肉瘤植入股骨会诱发持续的和运动诱发的骨癌相关疼痛行为。与给予赋形剂相比，腹腔注射I-RTX可显著减轻这些行为。蛋白质免疫印迹和逆转录-聚合酶链反应（RT-PCR）分析显示，肉瘤植入同侧的背根神经节（DRG）中TRPV1水平显著升高。免疫组织化学分析表明，骨肉瘤植入不仅导致DRG神经元中TRPV1阳性神经元的百分比增加（假手术小鼠为24.3±1.3%，骨肉瘤植入小鼠为31.2±1.3%，P<0.05），而且轮廓面积分布总体向右偏移。共定位研究表明，与假手术小鼠相比，骨肉瘤植入小鼠的DRG神经元中TRPV1与神经丝200 kD（NF200）和降钙素基因相关肽（CGRP）的共定位百分比增加，但与isolectin B4（IB4）的共定位百分比未增加（TRPV1和NF200从0.8±0.1%增加到2.1±0.3%，TRPV1和CGRP从21.1±1.3%增加到26.5±0.2%）。总之，TRPV1激活在骨癌疼痛的发生中起关键作用，骨癌会增加DRG神经元不同亚群中TRPV1的表达。这些发现可能会带来治疗骨癌疼痛的新策略。
