A rat model of bone cancer pain

Abstract

This study describes the first known model of bone cancer pain in the rat. Sprague-Dawley rats receiving intra-tibial injections of syngeneic MRMT-1 rat mammary gland carcinoma cells developed behavioural signs indicative of pain, including: mechanical allodynia, difference of weight bearing between hind paws and mechanical hyperalgesia. The development of the bone tumour and structural damage to the bone was monitored by radiological analysis, quantitative measurement of mineral content and histology. Intra-tibial injections of 3 x 10(3) or 3 x 10(4) syngeneic MRMT-1 cells produced a rapidly expanding tumour within the boundaries of the tibia, causing severe remodelling of the bone. Radiographs showed extensive damage to the cortical bone and the trabeculae by day 10-14 after inoculation of 3 x 10(3) MRMT-1 cells, and by day 20, the damage was threatening the integrity of the tibial bone. While both mineral content and mineral density decreased significantly in the cancerous bone, osteoclast numbers in the peritumoural compact bone remained unchanged. However, tartarate-resistant acid phosphatase staining revealed a large number of polykariotic cells, resembling those of osteoclasts within the tumour. No tumour growth was observed after the injection of heat-killed MRMT-1 cells. Intra-tibial injections of 3 x 10(3) or 3 x 10(4) MRMT-1 cells, heat-killed cells or vehicle did not show changes in body weight and core temperature over 19-20 days. The general activity of animals after injection with live or heat-killed MRMT-1 cells was higher than that of the control group, however, the activity of the MRMT-1 treated group declined during the progress of the disease. Rats receiving intra-tibial injections of MRMT-1 cells displayed the gradual development of mechanical allodynia and mechanical hyperalgesia/reduced weight bearing on the affected limb, beginning on day 12-14 or 10-12 following injection of 3 x 10(3) or 3 x 10(4) cells, respectively. These symptoms were not observed in rats receiving heat-killed cells or vehicle. Behavioural data suggest a reasonable time window for evaluation of anti-nociceptive agents between day 14 and 20 after cancer cell inoculation in this model. Acute treatment with morphine (1-3mg/kg, subcutanously (s.c.)) produced a dose-dependent reduction in the response frequency of hind paw withdrawal to von Frey filament stimulation 17 or 19 days following intra-tibial injections of 3 x 10(3) MRMT-1 cells. A significant reduction in the difference in hind limb weight bearing was also observed. Acute treatment with celebrex (10-30 mg/kg, s.c.) did not affect mechanical allodynia or difference in weight bearing in rats 20 days following treatment with 3 x 10(3) MRMT-1 cells. Although the pathophysiology of cancer pain is largely unknown, significant enhancement of glial fibrillary acidic protein (GFAP) staining in the corresponding segments of the ipsilateral spinal cord highlights the possible involvement of astrocytes. In summary, the induction of bone cancer in the rat by the syngeneic MRM...

Animal Models of Bone Metastasis

“…When injected intraosseously into Sprague-Dawley rats, osteolytic or mixed osteolytic/osteoblastic metastases developed. 25,79 Prostate Cancer It is estimated that prostate cancer resulted in 10% of all cancer deaths in American men in 2013. 121 Approximately 70% to 100% of patients who die due to prostate cancer have bone metastases.…”

“…When injected intraosseously into Sprague-Dawley rats, osteolytic or mixed osteolytic/osteoblastic metastases developed. 25,79 Simmons et al Canine cell lines-Four canine prostate cancer cell lines have been used to investigate bone metastasis: DPC-1, Ace-1, Leo, and Probasco cells. …”

Advances in understanding bone cancer pain

“…These models study tumors at different anatomic sites and of varied histological origin. Contemporary experimental models are based on direct injection of cancer cells into the medulla of the femur, humerus, and calcaneus [Honore et al, 2000c;Cain et al, 2001;Mach et al, 2002;Medhurst et al, 2002;Wacnik et al, 2003]. Intramedullary injection was first introduced at the end of the last decade by Schwei et al [1999] and has since evolved to incorporate a variety of tumor types used to observe the progression of bone cancer pain.…”

“…In rats, because of the large bone size, it is possible to inject tumor cells percutaneously into the tibia without performing a knee stifle [Medhurst et al, 2002]. With mice, because of diminutive bone size, tumor cells are injected into the humerus or femur after a surgical knee stifle [Wacnik et al, 2003;Goblirsch et al, 2004].…”

Animal Models of Cancer Pain

“…During the past decade, this lack of knowledge of the molecular, biochemical, and neurobiologic mechanisms that generate cancer pain has begun to be addressed, with the recent development of cancer pain models, 72,110,148,154,171,175,179,181,183,184 which are described in more detail later. These studies have resulted in the beginning of a mechanism-based understanding of the factors that generate and maintain cancer-induced pain.…”