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Behavioral, medical imaging and histopathological features of a new rat model of bone cancer pain.

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 (T(1)-Gd-DTPA) before pain detection. PET (Na(18)F) 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.

SUBMITTER: Dore-Savard L

PROVIDER: S-EPMC2966439 | biostudies-other | 2010 Oct

REPOSITORIES: biostudies-other

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Behavioral, medical imaging and histopathological features of a new rat model of bone cancer pain.

Doré-Savard Louis L Otis Valérie V Belleville Karine K Lemire Myriam M Archambault Mélanie M Tremblay Luc L Beaudoin Jean-François JF Beaudet Nicolas N Lecomte Roger R Lepage Martin M Gendron Louis L Sarret Philippe P

PloS one 20101029 10

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 perform ...[more]

PMID: 21048940

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Project description:Post-traumatic stress disorder (PTSD) has been associated with anxiety, memory impairments, enhanced fear, and hippocampal volume loss, although the relationship between these changes remain unknown. Single-prolonged stress (SPS) is a model for PTSD combining three forms of stress (restraint, swim, and anesthesia) in a single session that results in prolonged behavioral effects. Using pharmacogenetic ablation of adult neurogenesis in rats, we investigated the role of new neurons in the hippocampus in the long-lasting structural and behavioral effects of SPS. Two weeks after SPS, stressed rats displayed increased anxiety-like behavior and decreased preference for objects in novel locations regardless of the presence or absence of new neurons. Chronic stress produced by daily restraint for 2 or 6 hr produced similar behavioral effects that were also independent of ongoing neurogenesis. At a longer recovery time point, 1 month after SPS, rats with intact neurogenesis had normalized, showing control levels of anxiety-like behavior. However, GFAP-TK rats, which lacked new neurons, continued to show elevated anxiety-like behavior and enhanced serum corticosterone response to anxiogenic experience. Volume loss in ventral CA1 region of the hippocampus paralleled increases in anxiety-like behavior, occurring in all rats exposed to SPS at the early time point and only rats lacking adult neurogenesis at the later time point. In chronic stress experiments, volume loss occurred broadly throughout the dentate gyrus and CA1 after 6-hr daily stress but was not apparent in any hippocampal subregion after 2-hr daily stress. No effect of SPS was seen on cell proliferation in the dentate gyrus, but the survival of young neurons born a week after stress was decreased. Together, these data suggest that new neurons are important for recovery of normal behavior and hippocampal structure following a strong acute stress and point to the ventral CA1 region as a potential key mediator of stress-induced anxiety-like behavior.

Project description:BackgroundBisphosphonates are used to prevent the bone loss and fractures associated with osteoporosis, bone metastases, multiple myeloma, and osteogenesis deformans. Distal limb fractures cause regional bone loss with cutaneous inflammation and pain in the injured limb that can develop into complex regional pain syndrome (CRPS). Clinical trials have reported that antiresorptive bisphosphonates can prevent fracture-induced bone loss, inhibit serum inflammatory cytokine levels, and alleviate CRPS pain. Previously, we observed that the inhibition of inflammatory cytokines or adaptive immune responses attenuated the development of pain behavior in a rat fracture model of CRPS, and we hypothesized that bisphosphonates could prevent pain behavior, trabecular bone loss, postfracture cutaneous cytokine upregulation, and adaptive immune responses in this CRPS model.MethodsRats underwent tibia fracture and cast immobilization for 4 weeks and were chronically administered either subcutaneously perfused alendronate or oral zoledronate. Behavioral measurements included hindpaw von Frey allodynia, unweighting, warmth, and edema. Bone microarchitecture was measured by microcomputed tomography, and bone cellular activity was evaluated by static and dynamic histomorphometry. Spinal cord Fos immunostaining was performed, and skin cytokine (tumor necrosis factor, interleukin [IL]-1, IL-6) and nerve growth factor (NGF) levels were determined by enzyme immunoassay. Skin and sciatic nerve immunoglobulin levels were determined by enzyme immunoassay.ResultsRats with tibia fractures developed hindpaw allodynia, unweighting, warmth, and edema, increased spinal Fos expression and trabecular bone loss in the lumbar vertebra and bilateral distal femurs as measured by microcomputed tomography, increased trabecular bone resorption and osteoclast surface with decreased bone formation rates, increased cutaneous inflammatory cytokine and NGF expression, and elevated immunocomplex deposition in skin and nerve. Alendronate (60 μg/kg/d subcutaneously [s.c.]) or zoledronate (3 mg/kg/d orally) treatment for 28 days, started at the time of fracture, completely inhibited the development of hindpaw allodynia and reduced hindpaw unweighting by 44% ± 13% and 58% ± 5%, respectively. Orally administered zoledronate (3 mg/kg/d for 21 days) treatment also completely reversed established allodynia and unweighting when started at 4 weeks postfracture. Histomorphometric and microcomputed tomography analysis demonstrated that both the 3 and 60 μg/kg/d alendronate treatments reversed trabecular bone loss (an 88% ± 25% and 188% ± 39% increase in the ipsilateral distal femur BV/TV, respectively) and blocked the increase in osteoclast numbers and erosion surface observed in bilateral distal femurs and in L5 vertebra of the fracture rats. Alendronate treatment inhibited fracture-induced increases in hindpaw inflammatory mediators, reducing postfracture levels of tumor necrosis factor by 43% ± 9%, IL-1 by 60% ± 9%, IL-6 by 56% ± 14%, and NGF by 37% ± 14%, but had no effect on increased spinal cord Fos expression, or skin and sciatic nerve immunocomplex deposition.ConclusionsCollectively, these results indicate that bisphosphonate therapy inhibits pain, osteoclast activation, trabecular bone loss, and cutaneous inflammation in the rat fracture model of CRPS, data supporting the hypothesis that bisphosphonate therapy can provide effective multimodal treatment for CRPS.

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Behavioral, medical imaging and histopathological features of a new rat model of bone cancer pain.

Publications

Behavioral, medical imaging and histopathological features of a new rat model of bone cancer pain.

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