Optimization and characterization of a rat model of prostate cancer-induced bone pain using behavioural, pharmacological, radiological, histological and immunohistochemical methods

Muralidharan, Arjun, Wyse, Bruce D. and Smith, Maree T. (2013) Optimization and characterization of a rat model of prostate cancer-induced bone pain using behavioural, pharmacological, radiological, histological and immunohistochemical methods. Pharmacology Biochemistry and Behavior, 106 33-46. doi:10.1016/j.pbb.2013.02.020


Author Muralidharan, Arjun
Wyse, Bruce D.
Smith, Maree T.
Title Optimization and characterization of a rat model of prostate cancer-induced bone pain using behavioural, pharmacological, radiological, histological and immunohistochemical methods
Journal name Pharmacology Biochemistry and Behavior   Check publisher's open access policy
ISSN 0091-3057
1873-5177
Publication date 2013-02-20
Sub-type Article (original research)
DOI 10.1016/j.pbb.2013.02.020
Volume 106
Start page 33
End page 46
Total pages 14
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Collection year 2014
Language eng
Abstract 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 × 104 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.
Keyword μ-CT
Bone histology
Bone pain
Mechanical allodynia
Prostate cancer
Thermal hyperalgesia
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Pharmacy Publications
Centre for Integrated Preclinical Drug Development Publications
 
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Created: Mon, 25 Mar 2013, 15:49:40 EST by Myrtle Sahabandu on behalf of School of Pharmacy