Department of Anesthesiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, China.
Department of Nephrology, Tai' an Central Hospital, Taian, Shandong 271000, China.
Brain Res Bull. 2022 Jul;185:18-27. doi: 10.1016/j.brainresbull.2022.04.001. Epub 2022 Apr 8.
Patients with bone cancer pain (BCP) are more prone to aversion. which not only causes mental distress but also aggravates BCP. However, the mechanism of BCP-related aversion is still unclear. Previous studies have demonstrated that the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway of the rostral anterior cingulate cortex (rACC) plays an important role in the regulation of emotions related to chronic pain, such as neuropathic pain or inflammatory pain; however, few studies have investigated the role of this pathway in cancer pain. This study explored the role of BDNF in cancer pain-related aversion in the rACC and to determine whether N-methyl D-aspartate receptor subtype 2B (NR2B) and extracellular signal-regulated kinase (ERK)-cAMP response element-binding (CREB) signaling are involved in cancer pain-related aversion. A Sprague-Dawley rat model of BCP (one of the classic BCP models) was established, and the changes in pain aversion were detected by mechanical stimulation-induced conditioned place avoidance. Our findings confirmed that rats with BCP exhibited intense pain aversion accompanied by the up-regulated BDNF expression in the rACC. Additionally, the pain aversion of BCP rats was reduced while blocking the BDNF-TrkB. Furthermore, the expression of NR2B and phosphorylated ERK (pERK)/phosphorylated CREB (pCREB) were up-regulated with the development of pain aversion, whereas the use of NR2B blocker Ro25-6981, or ERK inhibitor U0126 could reduce the pain aversion. The expression of NR2B and pERK/pCREB were up-regulated after exogenous BDNF was injected into the rACC, whereas the expression levels of NR2B and pERK/pCREB were down-regulated after blocking the BDNF-TrkB signaling. In conclusion, the BDNF-TrkB signaling in the rACC mediates the generation of aversion in rats with BCP, which requires the involvement of NR2B and the ERK-CREB signaling pathway.
骨癌痛（BCP）患者更易出现厌恶感，不仅会导致精神痛苦，还会加重 BCP。然而，BCP 相关厌恶感的机制尚不清楚。先前的研究表明，额前皮质（rACC）中的脑源性神经营养因子（BDNF）-原肌球蛋白受体激酶 B（TrkB）信号通路在调节与慢性疼痛相关的情绪方面起着重要作用，如神经病理性疼痛或炎性疼痛；然而，很少有研究探讨该通路在癌症疼痛中的作用。本研究探讨了 BDNF 在 rACC 中与癌症相关厌恶感的关系，并确定 N-甲基-D-天冬氨酸受体 2B（NR2B）和细胞外信号调节激酶（ERK）-cAMP 反应元件结合（CREB）信号是否参与癌症相关的厌恶感。建立了骨癌痛（一种经典的骨癌痛模型）的 Sprague-Dawley 大鼠模型，通过机械刺激诱导的条件性位置回避来检测疼痛回避的变化。我们的研究结果证实，BCP 大鼠表现出强烈的疼痛回避，同时 rACC 中 BDNF 表达上调。此外，阻断 BDNF-TrkB 后，BCP 大鼠的疼痛回避减少。此外，随着疼痛回避的发展，NR2B 和磷酸化 ERK（pERK）/磷酸化 CREB（pCREB）的表达上调，而使用 NR2B 阻滞剂 Ro25-6981 或 ERK 抑制剂 U0126 可以减少疼痛回避。将外源性 BDNF 注射到 rACC 后，NR2B 和 pERK/pCREB 的表达上调，而阻断 BDNF-TrkB 信号后，NR2B 和 pERK/pCREB 的表达下调。综上所述，rACC 中的 BDNF-TrkB 信号介导了 BCP 大鼠产生厌恶感，这需要 NR2B 和 ERK-CREB 信号通路的参与。
