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

Muralidharan, Arjun; Wyse, Bruce D.; Smith, Maree T.

doi:10.1016/j.pbb.2013.02.020

Cited by 25 publications

(43 citation statements)

References 32 publications

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“…The presence of Ang II and the AT 2 receptor in adult rat lumbar dorsal root ganglia (DRGs) 27,29,40 is consistent with reports of AT 2 receptor mRNA in adult rat lumbar DRG neurons. 27,29 Using specific immunofluorescent antibodies, Ang II and the AT 2 receptors were colocalized with neuronal nuclei of substance P-containing small-tomedium sensory neurons in adult rat lumbar DRGs.…”

Section: Immunohistologysupporting

confidence: 88%

“…27,28 The mean ED 50 s for antiallodynia in the ipsilateral and contralateral hindpaws were 0.8 mg/kg and 1.8 mg/kg, respectively. 28 In PCIBP-rats, the corresponding mean ED 50 s for relief of thermal February 2016 · Volume 157 · Number 2 · Supplement 1 www.painjournalonline.com S35 hyperalgesia in the ipsilateral and contralateral hindpaws were 3.9 mg/kg and 5.5 mg/kg, respectively.…”

Section: Rat Model Of Prostate Cancer-induced Bone Pain: Mixed Periphmentioning

confidence: 95%

“…27,29 Using specific immunofluorescent antibodies, Ang II and the AT 2 receptors were colocalized with neuronal nuclei of substance P-containing small-tomedium sensory neurons in adult rat lumbar DRGs. The AT 2 receptor was also colocalized with neuronal nuclei of neurofilament 200kDa (NF200)-positive medium to large sensory DRG neurons, whereas Ang II was colocalized with a subset of these neurons.…”

Section: Immunohistologymentioning

confidence: 99%

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Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain

Smith

Anand

Rice

2016

Pain

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Neuropathic pain affects up to 10% of the general population, but drug treatments recommended for the treatment of neuropathic pain are associated with modest efficacy and/or produce dose-limiting side effects. Hence, neuropathic pain is an unmet medical need. In the past 2 decades, research on the pathobiology of neuropathic pain has revealed many novel pain targets for use in analgesic drug discovery programs. However, these efforts have been largely unsuccessful as molecules that showed promising pain relief in rodent models of neuropathic pain generally failed to produce analgesia in early phase clinical trials in patients with neuropathic pain. One notable exception is the angiotensin II type 2 (AT2) receptor that has clinical validity on the basis of a successful double-blind, randomized, placebo-controlled, clinical trial of EMA401, a highly selective, orally active, peripherally restricted AT2 receptor antagonist in patients with postherpetic neuralgia. In this study, we review research to date on target validation, efficacy, and mode of action of small molecule AT2 receptor antagonists in rodent models of peripheral neuropathic pain and in cultured human sensory neurons, the preclinical pharmacokinetics of these compounds, and the outcome of the above clinical trial.

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Section: Immunohistologysupporting

confidence: 88%

Section: Rat Model Of Prostate Cancer-induced Bone Pain: Mixed Periphmentioning

confidence: 95%

Section: Immunohistologymentioning

confidence: 99%

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Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain

Smith

Anand

Rice

2016

Pain

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“…Unilateral ITIs were performed in a manner similar to that described by others (Mao-Ying et al, 2006; Muralidharan et al, 2013) but with some modifications. Briefly, rats (~80–120 g) were anesthetized deeply with 3% isoflurane delivered in oxygen.…”

Section: Methodsmentioning

confidence: 99%

Optimization and In Vivo Profiling of a Refined Rat Model of Walker 256 Breast Cancer Cell-Induced Bone Pain Using Behavioral, Radiological, Histological, Immunohistochemical and Pharmacological Methods

et al. 2017

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In the majority of patients with advanced breast cancer, there is metastatic spread to bones resulting in pain. Clinically available drug treatments for alleviation of breast cancer-induced bone pain (BCIBP) often produce inadequate pain relief due to dose-limiting side-effects. A major impediment to the discovery of novel well-tolerated analgesic agents for the relief of pain due to bony metastases is the fact that most cancer-induced bone pain models in rodents relied on the systemic injection of cancer cells, causing widespread formation of cancer metastases and poor general animal health. Herein, we have established an optimized, clinically relevant Wistar Han female rat model of breast cancer induced bone pain which was characterized using behavioral assessments, radiology, histology, immunohistochemistry and pharmacological methods. In this model that is based on unilateral intra-tibial injection (ITI) of Walker 256 carcinoma cells, animals maintained good health for at least 66 days post-ITI. The temporal development of hindpaw hypersensitivity depended on the initial number of Walker 256 cells inoculated in the tibiae. Hindpaw hypersensitivity resolved after approximately 25 days, in the continued presence of bone tumors as evidenced by ex vivo histology, micro-computed tomography scans and immunohistochemical assessments of tibiae. A possible role for the endogenous opioid system as an internal factor mediating the self-resolving nature of BCIBP was identified based upon the observation that naloxone, a non-selective opioid antagonist, caused the re-emergence of hindpaw hypersensitivity. Bolus dose injections of morphine, gabapentin, amitriptyline and meloxicam all alleviated hindpaw hypersensitivity in a dose-dependent manner. This is a first systematic pharmacological profiling of this model by testing standard analgesic drugs from four important diverse classes, which are used to treat cancer induced bone pain in the clinical setting. Our refined rat model more closely mimics the pathophysiology of this condition in humans and hence is well-suited for probing the mechanisms underpinning breast cancer induced bone pain. In addition, the model may be suitable for efficacy profiling of new molecules from drug discovery programs with potential to be developed as novel agents for alleviation of intractable pain associated with disseminated breast cancer induced bony metastases.

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“…However, the beginning of pain behavior resolution at 20–25 days post-surgery is typically not due to tumor regression, but may involve neuro-immune mechanisms (Zhao et al, 2010; Xu et al, 2013; Huang et al, 2014). In previous work by others using different cancer cell lines, up regulation of the endogenous opioid system is implicated in spontaneous pain behavior resolution (Muralidharan et al, 2013). Similarly, endogenous opioid system could also have a role in Walker 256 cell-CIBP model (Li et al, 2016).…”

Section: Regression Of Tumor and Resolution Of Painmentioning

confidence: 97%

The Walker 256 Breast Cancer Cell- Induced Bone Pain Model in Rats

et al. 2016

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The majority of patients with terminal breast cancer show signs of bone metastasis, the most common cause of pain in cancer. Clinically available drug treatment options for the relief of cancer-associated bone pain are limited due to either inadequate pain relief and/or dose-limiting side-effects. One of the major hurdles in understanding the mechanism by which breast cancer causes pain after metastasis to the bones is the lack of suitable preclinical models. Until the late twentieth century, all animal models of cancer induced bone pain involved systemic injection of cancer cells into animals, which caused severe deterioration of animal health due to widespread metastasis. In this mini-review we have discussed details of a recently developed and highly efficient preclinical model of breast cancer induced bone pain: Walker 256 cancer cell- induced bone pain in rats. The model involves direct localized injection of cancer cells into a single tibia in rats, which avoids widespread metastasis of cancer cells and hence animals maintain good health throughout the experimental period. This model closely mimics the human pathophysiology of breast cancer induced bone pain and has great potential to aid in the process of drug discovery for treating this intractable pain condition.

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

Cited by 25 publications

References 32 publications

Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain

Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain

Optimization and In Vivo Profiling of a Refined Rat Model of Walker 256 Breast Cancer Cell-Induced Bone Pain Using Behavioral, Radiological, Histological, Immunohistochemical and Pharmacological Methods

The Walker 256 Breast Cancer Cell- Induced Bone Pain Model in Rats

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