Mathew Sumi Elizabeth, Madhusudanan Pallavi, Shankarappa Sahadev A
Center for Nanosciences & Molecular Medicine, Amrita Institute of Medical Sciences and Research Center, Amrita Vishwa Vidyapeetham University, Kochi, Kerala 682041, India.
J Pain Res. 2020 Jun 2;13:1305-1313. doi: 10.2147/JPR.S250198. eCollection 2020.
Cancer-induced bone pain (CIBP) is a debilitating chronic pain condition caused by injury to bone nerve terminals due to primary or metastasized bone tumors. Pain manifests as enhanced sensitivity, not only over the affected bone site but also at distal areas that share common nerve innervation with the tumor. In this study, we aim to understand how tumor-induced primary and distal pain sensitivities are affected by bupivacaine-induced block of bone nerve endings in a rat model of CIBP.
MRMT-1 breast cancer cells were injected into the proximal segment of tibia in female Sprague-Dawley rats. Radiograms and micro-CT images were obtained to confirm tumor growth. Bupivacaine was injected peritumorally at day 7 or day 14 post-tumor induction, and withdrawal thresholds in response to pressure and punctate mechanical stimulus were recorded from the knee and hind-paw, respectively. Immunohistochemical studies for the determination of ATF3 and GFAP expression in DRG and spinal cord sections were performed.
Rats developed primary and distal hyperalgesia after MRMT-1 administration that was sustained for 2 weeks. Peritumoral administration of bupivacaine in 7-day post-tumor-induced (PTI) rats resulted in a reversal of both primary and distal hyperalgesia for 20-30 mins. However, bupivacaine failed to reverse distal hyperalgesia in 14 day-PTI rats. ATF3 and GFAP expression were much enhanced in 14 day-PTI animals, compared to 7 day-PTI group.
Results from this study strongly suggest that distal hyperalgesia of late-stage CIBP demonstrates differential characteristics consistent with neuropathic pain as compared to early stage, which appears more inflammatory in nature.
癌症诱发的骨痛（CIBP）是一种使人衰弱的慢性疼痛病症，由原发性或转移性骨肿瘤导致骨神经末梢损伤引起。疼痛不仅表现为患骨部位的敏感性增强，还表现为与肿瘤共享共同神经支配的远端区域的敏感性增强。在本研究中，我们旨在了解在CIBP大鼠模型中，布比卡因诱导的骨神经末梢阻滞如何影响肿瘤诱导的原发性和远端疼痛敏感性。
将MRMT-1乳腺癌细胞注射到雌性Sprague-Dawley大鼠胫骨的近端。获取X线片和微型CT图像以确认肿瘤生长。在肿瘤诱导后第7天或第14天在肿瘤周围注射布比卡因，并分别记录膝关节和后爪对压力和点状机械刺激的撤针阈值。进行免疫组织化学研究以测定背根神经节（DRG）和脊髓切片中ATF3和GFAP的表达。
给予MRMT-1后，大鼠出现原发性和远端痛觉过敏，并持续2周。在肿瘤诱导后7天（PTI）的大鼠中，在肿瘤周围给予布比卡因可使原发性和远端痛觉过敏在20 - 30分钟内得到逆转。然而，布比卡因未能逆转肿瘤诱导后14天的大鼠的远端痛觉过敏。与7天PTI组相比，14天PTI动物中ATF3和GFAP的表达明显增强。
本研究结果强烈表明，与早期相比，晚期CIBP的远端痛觉过敏表现出与神经性疼痛一致的不同特征，早期似乎更具炎症性质。
