Protease-Activated Receptor 2 Antagonist Potentiates Analgesic Effects of Systemic Morphine in a Rat Model of Bone Cancer Pain

Abstract Bone cancer pain (BCP) is a common chronic pain that is caused by a primary or metastatic bone tumor. More detailed molecular mechanisms of BCP are warranted. In this study, we established a BCP rat model. The von Frey hair test, body weight, and hematoxylin and eosin staining were employed. We screened differentially expressed circRNAs (DECs) between the BCP group and sham group. The results revealed that 850 DECs were significantly up-regulated and 644 DECs were significantly down-regulated in the BCP group. Furthermore, we identified 1177 differentially expressed genes (DEGs) significantly up-regulated and 565 DEGs significantly down-regulated in the BCP group. Gene Ontology annotation of all 1742 DEGs revealed that biological regulation of metabolic processes, cellular processes, and binding were the top enriched terms. For Kyoto Encyclopedia of Genes and Genomes analysis, phagosome, HTLV-I infection, proteoglycans in cancer, and herpes simplex infection were significantly enriched in this study. In addition, we identified four selected circRNAs, chr6:72418120|72430205, chr20:7561057|7573740, chr18:69943105|69944476, and chr5:167516581|167558250, by quantitative real time PCR. chr6:72418120|72430205 (circStrn3) was selected for further study based on expression level and the circRNA–miRNA–mRNA network table. Western blot analysis suggested that knockdown of circStrn3 could effectively induce Walker 256 cell apoptosis. In summary, our study provided a more in-depth understanding of the molecular mechanisms of BCP.

Download Full-text

Levo-Tetrahydropalmatine Attenuates Bone Cancer Pain by Inhibiting Microglial Cells Activation

Mediators of Inflammation ◽

10.1155/2015/752512 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 9

Author(s):

Mao-yin Zhang ◽

Yue-peng Liu ◽

Lian-yi Zhang ◽

Dong-mei Yue ◽

Dun-yi Qi ◽

...

Keyword(s):

Spinal Cord ◽

Cancer Pain ◽

Mechanical Allodynia ◽

Thermal Hyperalgesia ◽

Bone Cancer ◽

Microglial Cells ◽

Bone Cancer Pain ◽

Enzyme Linked Immunosorbent Assay ◽

Analgesic Effects ◽

Before And After

Objective. The present study is to investigate the analgesic roles of L-THP in rats with bone cancer pain caused by tumor cell implantation (TCI).Methods. Thermal hyperalgesia and mechanical allodynia were measured at different time points before and after operation. L-THP (20, 40, and 60 mg/kg) were administrated intragastrically at early phase of postoperation (before pain appearance) and later phase of postoperation (after pain appearance), respectively. The concentrations of TNF-α, IL-1β, and IL-18 in spinal cord were measured by enzyme-linked immunosorbent assay. Western blot was used to test the activation of astrocytes and microglial cells in spinal cord after TCI treatment.Results. TCI treatment induced significant thermal hyperalgesia and mechanical allodynia. Administration of L-THP at high doses significantly prevented and/or reversed bone cancer-related pain behaviors. Besides, TCI-induced activation of microglial cells and the increased levels of TNF-αand IL-18 were inhibited by L-THP administration. However, L-THP failed to affect TCI-induced astrocytes activation and IL-1βincrease.Conclusion. This study suggests the possible clinical utility of L-THP in the treatment of bone cancer pain. The analgesic effects of L-THP on bone cancer pain maybe underlying the inhibition of microglial cells activation and proinflammatory cytokines increase.

Download Full-text

Antinociceptive Effect of Intrathecal Injection of Genetically Engineered Human Bone Marrow Stem Cells Expressing the Human Proenkephalin Gene in a Rat Model of Bone Cancer Pain

Pain Research and Management ◽

10.1155/2017/7346103 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Yi Sun ◽

Yuke Tian ◽

Haifeng Li ◽

Dengwen Zhang ◽

Qiang Sun

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Gene Transfer ◽

Cancer Pain ◽

Rat Model ◽

Bone Cancer ◽

Genetically Engineered ◽

Human Bone ◽

Human Bone Marrow ◽

Bone Cancer Pain

Background. This study aimed to investigate the use of human bone marrow mesenchymal stem cells (hBMSCs) genetically engineered with the human proenkephalin (hPPE) gene to treat bone cancer pain (BCP) in a rat model.Methods. Primary cultured hBMSCs were passaged and modified with hPPE, and the cell suspensions (6 × 106) were then intrathecally injected into a rat model of BCP. Paw mechanical withdrawal threshold (PMWT) was measured before and after BCP. The effects of hPPE gene transfer on hBMSC bioactivity were analyzed in vitro and in vivo.Results. No changes were observed in the surface phenotypes and differentiation of hBMSCs after gene transfer. The hPPE-hBMSC group showed improved PMWT values on the ipsilateral side of rats with BCP from day 12 postoperatively, and the analgesic effect was reversed by naloxone. The levels of proinflammatory cytokines such as IL-1βand IL-6 were ameliorated, and leucine-enkephalin (L-EK) secretion was augmented, in the hPPE-engineered hBMSC group.Conclusion. The intrathecal administration of BMSCs modified with the hPPE gene can effectively relieve pain caused by bone cancer in rats and might be a potentially therapeutic tool for cancer-related pain in humans.

Download Full-text

Analgesic effects of neurotensin agonists in a rat bone cancer pain model

10.1101/089169 ◽

2016 ◽

Author(s):

Louis Dore-Savard ◽

Pascal Tetreault ◽

Melisange Roux ◽

Marylie Martel ◽

Myriam Lemire ◽

...

Keyword(s):

Cancer Pain ◽

Weight Bearing ◽

Bone Cancer ◽

Opioid Analgesics ◽

Bone Cancer Pain ◽

Intractable Pain ◽

Analgesic Effects ◽

Selective Agonist ◽

Neurotensin Receptors ◽

Pain Models

Bone metastases are a source of intractable pain, resistant to conventional opioid and non-opioid analgesics. The neurotensin system represents a potential pathway toward bone cancer pain (BCP) relieve via the inhibition of its receptors NTS1 and NTS2. Capitalizing on our recent results using neurotensin analogs in inflammatory and neuropathic pain models, we here show, for the first time, a potential role for neurotensin receptors agonists in the treatment of BCP. The novel non-selective agonist JMV-2009 (300 μg/kg) reversed mechanical allodynia in our rodent BCP model at both early and late stages of the disease. The NTS2-selective agonist JMV-431 (90 μg/kg), in addition to anti-allodynia, also had an effect on weight bearing deficits. In parallel, we tested proven analgesics from several classes to put the effect of neurotensin analogs in perspective and found that morphine (3 mg/kg), tramadol (15 mg/kg) and amitriptyline (10 mg/kg) had mild effects on BCP while the cannabinoid nabilone (1 mg/kg) significantly reversed both allodynia and weight bearing deficits. Taken together, our results affirm the potential of the modulation of the neurotensin system for the development of new analgesics for the treatment of bone cancer pain.

Download Full-text

Spinal glial activation in a new rat model of bone cancer pain produced by prostate cancer cell inoculation of the tibia

Pain ◽

10.1016/j.pain.2005.08.001 ◽

2005 ◽

Vol 118 (1) ◽

pp. 125-136 ◽

Cited By ~ 138

Author(s):

Rui-Xin Zhang ◽

Bing Liu ◽

Linbo Wang ◽

Ke Ren ◽

Jian-Tian Qiao ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Pain ◽

Cancer Cell ◽

Rat Model ◽

Prostate Cancer Cell ◽

Bone Cancer ◽

Glial Activation ◽

Bone Cancer Pain ◽

Cell Inoculation

Download Full-text

Behavioral, Medical Imaging and Histopathological Features of a New Rat Model of Bone Cancer Pain

PLoS ONE ◽

10.1371/journal.pone.0013774 ◽

2010 ◽

Vol 5 (10) ◽

pp. e13774 ◽

Cited By ~ 35

Author(s):

Louis Doré-Savard ◽

Valérie Otis ◽

Karine Belleville ◽

Myriam Lemire ◽

Mélanie Archambault ◽

...

Keyword(s):

Medical Imaging ◽

Cancer Pain ◽

Rat Model ◽

Bone Cancer ◽

Bone Cancer Pain ◽

Histopathological Features

Download Full-text

Preconditioning with hydrogen sulfide prevents bone cancer pain in rats through a proliferator-activated receptor gamma/p38/Jun N-terminal kinase pathway

Experimental Biology and Medicine ◽

10.1177/1535370217740859 ◽

2017 ◽

Vol 243 (1) ◽

pp. 57-65 ◽

Cited By ~ 3

Author(s):

Li Zhuang ◽

Ke Li ◽

Gaowei Wang ◽

Tao Shou ◽

Chunlin Gao ◽

...

Keyword(s):

Spinal Cord ◽

Cancer Pain ◽

Rat Model ◽

Mechanical Allodynia ◽

Antinociceptive Effect ◽

Thermal Hyperalgesia ◽

Bone Cancer ◽

Bone Cancer Pain ◽

Kinase Pathway

Bone cancer pain (BCP) is a severe type of hyperpathic pain occurring with primary bone tumors or advanced cancers which metastasize to bones. BCP can detrimentally reduce quality of life and presents a challenge to modern medicine. Studies have shown that exogenous H2S may act as a neuroprotectant to protect against some diseases in central nervous system. The preset study aimed to investigate the antinociceptive effect of H2S in BCP. We first measured the changes of serum H2S in patients with BCP and analyzed the relationship between them, then investigated the effect of H2S preconditioning on BCP, and explored the mechanism in rat model. Our results revealed that serum H2S level was negatively correlated with pain scores. In the rat model of BCP, preconditioning with H2S significantly reduced BCP, demonstrated by the decrease of thermal hyperalgesia and mechanical allodynia. The mechanism of H2S preconditioning may involve microglia deactivation and inflammation inhibition in the spinal cord, in which the proliferator-activated receptor gamma/p38/Jun N-terminal kinase pathway is activated. Impact statement Bone cancer pain (BCP) significantly decreases the life quality of patients or their life expectancy and causes a severe health burden to the society. However, as the exact mechanism of BCP is still poorly understood, no effective treatment has been developed yet. There are some pain medicines now, but they have some inevitable side effects. Additional therapeutic strategies are urgently needed. First, we revealed that preconditioning with H2S significantly reduced BCP, demonstrated by the decrease of thermal hyperalgesia and mechanical allodynia. Second, the mechanism of H2S preconditioning was elucidated. It may involve microglia deactivation and inflammation inhibition in the spinal cord, in which the proliferator-activated receptor gamma/p38/Jun N-terminal kinase pathway is activated. This novel finding may significantly help us to understand the difference between the roles of endogenous H2S and exogenous H2S in the development of BCP and present us a new strategy of pain management.

Download Full-text