Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP). Rostral ventromedial medulla (RVM) is a critical component of descending nociceptive facili...Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP). Rostral ventromedial medulla (RVM) is a critical component of descending nociceptive facilitation circuitry, but so far the mechanisms are poorly known. In this study, we investigated the role of RVM glial activation in the descending nociceptive facilitation circuitry in a CIBP rat model. CIBP rats showed significant activation of microglia and astrocytes, and also up-regulation of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and pro-inflammatory mediators released by glial cells (IL-1β, IL-6, TNF-α and brain-derived neurotrophic factor) in the RVM. Stereotaxic microinjection of the glial inhibitors (minocycline and fluorocitrate) into CIBP rats’ RVM could reverse the glial activation and significantly attenuate mechanical allodynia in a time-dependent manner. RVM microinjection of p38 MAPK inhibitor (SB203580) abolished the activation of microglia, reversed the associated up-regulation of proinflammatory mediators and significantly attenuated mechanical allodynia. Taken together, these results suggest that RVM glial activation is involved in the pathogenesis of CIBP. RVM microglial p38 MAPK signaling pathway is activated and leads to the release of downstream pro-inflammatory mediators, which contribute to the descending facilitation of CIBP.展开更多
Cancer-induced bone pain(CIBP)is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone metastasis.CIBP constitutes a specific pain state with distinct characteristics;however,it shares similari...Cancer-induced bone pain(CIBP)is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone metastasis.CIBP constitutes a specific pain state with distinct characteristics;however,it shares similarities with inflammatory and neuropathic pain.At present,although various therapies have been developed for this condition,complete relief from CIBP in patients with cancer is yet to be achieved.Hence,it is urgent to study the mechanism underlying CIBP to develop efficient analgesic drugs.Herein,we focused on the peripheral mechanism associated with the initiation of CIBP,which involves tissue injury in the bone and changes in the tumor microenvironment(TME)and dorsal root ganglion.The nerve–cancer and cancer–immunocyte cross-talk in the TME creates circumstances that promote tumor growth and metastasis,ultimately leading to CIBP.The peripheral mechanism of CIBP and current treatments as well as potential therapeutic targets are discussed in this review.展开更多
Bone metastasis,a life-threatening complication of advanced breast cancer,is often accompanied by debilitating pain(cancer-induced bone pain,CIBP)that severely impairs life quality and survival.The concurrent treatmen...Bone metastasis,a life-threatening complication of advanced breast cancer,is often accompanied by debilitating pain(cancer-induced bone pain,CIBP)that severely impairs life quality and survival.The concurrent treatment of bone metastases and CIBP remains a clinical challenge because the therapeutic options are limited.In this study,we construct a near-infrared light-activated nano-therapeutic system to meet this conundrum.In detail,sorafenib(SRF)and photosensitizer(chlorin e6,Ce6)are encapsulated into mesoporous hydroxyapatite nanoparticles(HANPs),which are further functionalized with hyaluronic acid(HA)to obtain HA-SRF/Ce6@HANPs system.The designed nanoplatform destroys tumor cells in vitro and in vivo via the synergism of SRF(interrupting the exchange of cystine/glutamate by inhibiting SLC7A11)and photodynamic therapy(PDT,inducing reactive oxygen species generation).The decrease in tumor burden and reduction of extracellular glutamate significantly attenuate CIBP in mice model with developing bone cancer.Moreover,the combination of HA-SRF/Ce6@HANPs and PDT inhibit osteoclasts activation,promote osteoblast differentiation and accelerate bone repair.Overall,the nanoagent with good biocompatibility may provide an effective therapy method for the concurrent treatment of breast cancer bone metastasis and CIBP.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.30901396,No.81070890,No.30872441and No.81171259)
文摘Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP). Rostral ventromedial medulla (RVM) is a critical component of descending nociceptive facilitation circuitry, but so far the mechanisms are poorly known. In this study, we investigated the role of RVM glial activation in the descending nociceptive facilitation circuitry in a CIBP rat model. CIBP rats showed significant activation of microglia and astrocytes, and also up-regulation of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and pro-inflammatory mediators released by glial cells (IL-1β, IL-6, TNF-α and brain-derived neurotrophic factor) in the RVM. Stereotaxic microinjection of the glial inhibitors (minocycline and fluorocitrate) into CIBP rats’ RVM could reverse the glial activation and significantly attenuate mechanical allodynia in a time-dependent manner. RVM microinjection of p38 MAPK inhibitor (SB203580) abolished the activation of microglia, reversed the associated up-regulation of proinflammatory mediators and significantly attenuated mechanical allodynia. Taken together, these results suggest that RVM glial activation is involved in the pathogenesis of CIBP. RVM microglial p38 MAPK signaling pathway is activated and leads to the release of downstream pro-inflammatory mediators, which contribute to the descending facilitation of CIBP.
基金supported by the Zhongshan-Fudan Joint Innovation Center,Zhongshan,Guangdong Province,China(528437)the National Natural Science Foundation of China(82271258,82271248,82204830,81971056)+1 种基金Innovative Research Team of High-level Local Universities in Shanghai,Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJ Lab,Shanghai Center for Brain Science and Brain-Inspired Technology.
文摘Cancer-induced bone pain(CIBP)is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone metastasis.CIBP constitutes a specific pain state with distinct characteristics;however,it shares similarities with inflammatory and neuropathic pain.At present,although various therapies have been developed for this condition,complete relief from CIBP in patients with cancer is yet to be achieved.Hence,it is urgent to study the mechanism underlying CIBP to develop efficient analgesic drugs.Herein,we focused on the peripheral mechanism associated with the initiation of CIBP,which involves tissue injury in the bone and changes in the tumor microenvironment(TME)and dorsal root ganglion.The nerve–cancer and cancer–immunocyte cross-talk in the TME creates circumstances that promote tumor growth and metastasis,ultimately leading to CIBP.The peripheral mechanism of CIBP and current treatments as well as potential therapeutic targets are discussed in this review.
基金financially supported by the National Natural Science Foundation of China(No.82001189)The Project Tackling of Key Scientific and Technical Problems of Henan Provine(No.232102311163).
文摘Bone metastasis,a life-threatening complication of advanced breast cancer,is often accompanied by debilitating pain(cancer-induced bone pain,CIBP)that severely impairs life quality and survival.The concurrent treatment of bone metastases and CIBP remains a clinical challenge because the therapeutic options are limited.In this study,we construct a near-infrared light-activated nano-therapeutic system to meet this conundrum.In detail,sorafenib(SRF)and photosensitizer(chlorin e6,Ce6)are encapsulated into mesoporous hydroxyapatite nanoparticles(HANPs),which are further functionalized with hyaluronic acid(HA)to obtain HA-SRF/Ce6@HANPs system.The designed nanoplatform destroys tumor cells in vitro and in vivo via the synergism of SRF(interrupting the exchange of cystine/glutamate by inhibiting SLC7A11)and photodynamic therapy(PDT,inducing reactive oxygen species generation).The decrease in tumor burden and reduction of extracellular glutamate significantly attenuate CIBP in mice model with developing bone cancer.Moreover,the combination of HA-SRF/Ce6@HANPs and PDT inhibit osteoclasts activation,promote osteoblast differentiation and accelerate bone repair.Overall,the nanoagent with good biocompatibility may provide an effective therapy method for the concurrent treatment of breast cancer bone metastasis and CIBP.
