Abstract
Pre-clinical bone cancer pain models mimicking the human condition are required to respond to clinical realities. Breast or prostate cancer patients coping with bone metastases experience intractable pain, which affects their quality of life. Advanced monitoring is thus required to clarify bone cancer pain mechanisms and refine treatments. In our model of rat femoral mammary carcinoma MRMT-1 cell implantation, pain onset and tumor growth were monitored for 21 days. The surgical procedure performed without arthrotomy allowed recording of incidental pain in free-moving rats. Along with the gradual development of mechanical allodynia and hyperalgesia, behavioral signs of ambulatory pain were detected at day 14 by using a dynamic weight-bearing apparatus. Osteopenia was revealed from day 14 concomitantly with disorganization of the trabecular architecture (µCT). Bone metastases were visualized as early as day 8 by MRI (T1-Gd-DTPA) before pain detection. PET (Na18F) co-registration revealed intra-osseous activity, as determined by anatomical superimposition over MRI in accordance with osteoclastic hyperactivity (TRAP staining). Pain and bone destruction were aggravated with time. Bone remodeling was accompanied by c-Fos (spinal) and ATF3 (DRG) neuronal activation, sustained by astrocyte (GFAP) and microglia (Iba1) reactivity in lumbar spinal cord. Our animal model demonstrates the importance of simultaneously recording pain and tumor progression and will allow us to better characterize therapeutic strategies in the future.
Highlights
Among cancers with a poor prognosis, those originating from breast, lung and prostate commonly metastasize to the skeleton [1,2]
The impact of surgery was minimized by implantation at this anatomical site, which reduces the chances of patellar ligament or joint damage
As measured with the Randall-Selitto test, a significant difference was observed between ipsilateral and contralateral paw withdrawal thresholds from day 18 (30.9610.8 g, p,0.001) to day 21 (25.767.6 g, p,0.01; Fig. 1B). These results demonstrate that measurable touch-evoked pain behaviors develop after the injection of carcinoma cells into the femur, as previously demonstrated with MRMT-1 cell implantation in the tibia [24]
Summary
Among cancers with a poor prognosis, those originating from breast, lung and prostate commonly metastasize to the skeleton [1,2]. Bone cancer pain originates from nerve compression, ischemia and release of proinflammatory substances by the tumor and cells from the bone environment [5]. Compensative and anarchic bone formation by osteoblasts compresses free nerve terminal endings scattered in the bone marrow, matrix and periosteum [10], leading to the genesis and maintenance of pain. The association of those phenomena produces a unique mechanical and neurochemical onset that goes beyond the combination of neuropathic and inflammatory pain [11]
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