Involvement of Spinal Bv8/Prokineticin 2 in a Rat Model of Cancer‐Induced Bone Pain

Abstract

Cancer-induced bone pain (CIBP) is seriously disruptive to the quality of life in cancer patients, and present therapies are limited. The Bv8/prokineticin 2, a new family of chemokines, has been demonstrated to be involved in inflammatory and neuropathic pain. However, whether it is involved in CIBP remains unclear. This study was designed to examine whether spinal Bv8 was involved in the development of CIBP in rats. A rat CIBP model was constructed by injecting Walker 256 carcinoma cells into the medullary cavity of rat tibia. Tibia inoculation with Walker 256 tumour cells resulted in the development of mechanical hyperalgesia. Compared with sham rats, spinal Bv8 mRNA and protein levels were markedly and time-dependently increased in CIBP rats. Intrathecal administration of Bv8 neutralizing antibody (5 ng) could markedly attenuate pain behaviour as well as up-regulation of spinal TNF-a expression at day 18 after inoculation. Intrathecal pre-treatment with synthetic Bv8 (50 pg) almost completely abolished these effects. These data suggested that spinal Bv8/prokineticin 2 participated in the development of CIBP. Targeting of spinal Bv8 might be a promising strategy for the management of cancer-induced bone pain. Many common types of cancer, such as prostate, breast and lung, have a tendency to metastasize to bone. Tumour metas-tasis to bone can subsequently cause cancer-induced bone pain (CIBP) [1,2]. CIBP is a complicated pain state including a combination of spontaneous pain, background pain and incident pain. CIBP is one of the most feared and enfeebling symptoms and is seriously disruptive to the patients' quality of life. Although numerous methods including chemotherapy, radiotherapy, nerve blocks and analgesic agents are used to control CIBP, researches have reported that at least 20-40% of CIBP is not adequately controlled because current therapies are both insufficient and associated with undesirable adverse effects [3]. Currently, few analgesic treatments have emerged because the molecular and cellular mechanisms underlying the development of CIBP still remain unclear [4]. Bv8 (also named prokineticin 2), a new family of chemo-kines, has attracted growing interest since its identification in 1999 [5]. It acts on two G protein-coupled receptors called prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2) [6]. Bv8 is highly expressed by neutrophils and other inflammatory cells, and it is considered as a new pronocicep-tive mediator in the site of inflammation [7]. Recently, Bv8 and its receptors were found broadly distributed in spinal dor-sal horn and dorsal root ganglia (DRG), indicating that Bv8/ PKRs may play an important role in the transmission of noci-ceptive perception [8,9]. Intraplantar injection of Bv8 induces a localized hyperalgesia by reducing the nociceptive thresholds to thermal, chemical and mechanical stimuli [5,10]. Recent studies have indicated that Bv8 is involved in inflammatory and neuropathic pain [7,11]. However, CIBP is a mixed-mechanism pain state that is not totally ...

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

“…Although, this model involving ITI of Walker 256 cells in rats might not exactly mimic the metastatic spread of breast cancer to the axial skeleton in humans (Kurth et al, 2001, 2002), it provides great insights into the pathobiology and mechanisms of breast CIBP and is hence used very widely in experimental research (Du et al, 2015; Hang et al, 2015; Hu S. et al, 2015; Liu et al, 2015; Lu et al, 2015). Undoubtedly, it is one of the most suitable preclinical models for efficacy assessment of novel compounds from discovery programs aimed at identifying drugs with potential to alleviate breast CIBP in humans.…”

“…In addition to being a reproducible method for inducing skeletal metastasis (Blouin et al, 2005; Mao-Ying et al, 2006; Badraoui et al, 2009), this model mimics key features of human breast CIBP, including pharmacological profile (Mao-Ying et al, 2006, 2012; Cao et al, 2010). Walker 256 cells can be used in a variety of rat strains (Hang et al, 2015; Lu et al, 2015) because these cells produce uniformly rapid growth, show very little regression, and are readily adaptable (Lewis et al, 2013; Oliveira and Gomes-Marcondes, 2016). …”

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 features of any given animal model of CIBP thus require characterisation using standardized protocols to reduce the number of variables affecting the experiments to enhance experimental reproducibility. In the present work, W256 cells were selected as they are widely used in research (Justice, 1985; Brigatte et al, 2007) and because of the ease with which they can be cultured, standardized and reproduced (McEuen and Thomson, 1933; Hang et al, 2015). A comparative summary of previous studies using the W256 cell-induced bone pain model in rats, has been comprehensively provided in a recent review (Shenoy et al, 2016).…”

Monocyte chemoattractant protein-1 contributes to morphine tolerance in rats with cancer-induced bone pain

“…Cancer-induced bone pain seriously impairs the quality of life of cancer patients; however, there are currently no effective therapies available for bone pain (29). In the present study, the mRNA expression levels of MCP-1 and its receptor CCR2 were found to be upregulated in the spinal cord of MTBP rats (BM group).…”