Activation of PI3Kγ/Akt pathway mediates bone cancer pain in rats

Bone cancer pain (BCP) is one of the most common and severe complications in patients suffering from primary bone cancer or metastatic bone cancer such as breast, prostate, or lung, which profoundly compromises their quality of life. Emerging lines of evidence indicate that central sensitization is required for the development and maintenance of BCP. However, the underlying mechanisms are largely unknown. In this study, weinvestigated the role of PI3K/Akt in the central sensitization in rats with tumor cell implantation in the tibia, a widely used model of BCP. Our results showed that PI3K and its downstream target pAkt were up-regulated in a time-dependent manner and distributed predominately in the superficial layers of the spinal dorsal horn neurons, astrocytes and a minority of microglia, and were colocalized with non-peptidergic, calcitonin gene-related peptide-peptidergic, and A-type neurons in dorsal root ganglion ipsilateral to tumor cell inoculation in rats. Inhibition of spinal PI3K suppressed BCP-associated behaviors and the up-regulation of pAkt in the spinal cord and dorsal root ganglion. This study suggests that PI3K/Akt signal pathway mediates BCP in rats.

骨癌疼痛（BCP）是原发性骨癌或转移性骨癌（如乳腺癌、前列腺癌或肺癌）患者最常见且严重的并发症之一，这极大地损害了他们的生活质量。新出现的一系列证据表明，中枢敏化是骨癌疼痛发生和维持所必需的。然而，其潜在机制在很大程度上尚不清楚。在本研究中，我们研究了PI3K/Akt在胫骨肿瘤细胞植入大鼠中枢敏化中的作用，胫骨肿瘤细胞植入是一种广泛使用的骨癌疼痛模型。我们的结果显示，PI3K及其下游靶点pAkt以时间依赖性方式上调，并主要分布在脊髓背角神经元、星形胶质细胞的浅层以及少数小胶质细胞中，且在大鼠肿瘤细胞接种同侧的背根神经节中与非肽能、降钙素基因相关肽肽能和A型神经元共定位。脊髓PI3K的抑制可抑制与骨癌疼痛相关的行为以及脊髓和背根神经节中pAkt的上调。本研究表明，PI3K/Akt信号通路介导了大鼠的骨癌疼痛。