The major limitation of currently utilized rodent models of prostate cancer (PCa)-induced bone pain (PCIBP) involving intra-osseous injection of PCa cells, is their relatively short-term applicability due to progressive deterioration of animal health necessitating euthanasia. Here, we describe establishment of an optimized rat model of PCIBP where good animal health was maintained for at least 90-days following unilateral intra-tibial injection (ITI) of PCa cells. We have characterized this model using behavioral, pharmacological, radiological, histological and immunohistochemical methods. Our findings show that following unilateral ITI of 4×10(4) AT3B PCa cells (APCCs), there was temporal development of bilateral hindpaw hypersensitivity that was fully developed between days 14 and 21 post-ITI. Although there was apparent spontaneous reversal of bilateral hindpaw sensitivity that was maintained until at least day 90 post-ITI, administration of bolus doses of the opioid receptor antagonist, naloxone, rescued the pain phenotype in these animals. Hence, upregulation of endogenous opioid signaling mechanisms appears to underpin apparent spontaneous resolution of hindpaw hypersensitivity. Importantly, the histological and radiological assessments confirmed that tumor formation and development of osteosclerotic metastases was confined to the APCC-injected tibial bones. In our rat model of PCIBP, single bolus doses of morphine, gabapentin, meloxicam and amitriptyline produced dose-dependent relief of mechanical allodynia and thermal hyperalgesia in the bilateral hindpaws. The optimized rat model of PCIBP characterized herein has potential to provide new insights into the pathophysiological mechanisms associated with long-term (mal)adaptive pain due to advanced PCa-induced bony metastases and for screening novel compounds with potential for improved alleviation of this condition.
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