Activation of <scp>PI</scp>3Kγ/Akt pathway mediates bone cancer pain in rats

Guan, Xue-Hai; Fu, Qiaochu; Xiong, Bingrui; Song, Zhenpeng; Shu, Bin; Bu, Huilian; Xu, Bing; Manyande, Anne; Cao, Fei; Tian, Yuan

doi:10.1111/jnc.13139

Cited by 37 publications

(29 citation statements)

References 47 publications

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“…Guedon et al presented several possible mechanisms that could drive bone cancer-induced CUT hypersensitivity, 1 including DRG dysfunction, 33,34 spinal sensitization 35,36 and central sensitization. 2,37,38 All three mechanisms could result in altered descending modulation and ascending facilitation of noxious and nonnoxious sensory input. 1 In our study, injection of L-glutamic acid or SSZ into the quadriceps femoris muscle changed the mechanical threshold and spiking number of HTM and LTM sensory neurons within the first 5 minutes.…”

Section: Discussionmentioning

confidence: 99%

Bone cancer-induced pain is associated with glutamate signalling in peripheral sensory neurons

Zhu

Linher‐Melville

et al. 2020

Mol Pain

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We previously identified that several cancer cell lines known to induce nociception in mouse models release glutamate in vitro. Although the mechanisms of glutamatergic signalling have been characterized primarily in the central nervous system, its importance in the peripheral nervous system has been recognized in various pathologies, including cancer pain. We therefore investigated the effect of glutamate on intracellular electrophysiological characteristics of peripheral sensory neurons in an immunocompetent rat model of cancer-induced pain based on surgical implantation of mammary rat metastasis tumour-1 cells into the distal epiphysis of the right femur. Behavioural evidence of nociception was detected using von Frey tactile assessment. Activity of sensory neurons was measured by intracellular electrophysiological recordings in vivo. Glutamate receptor expression at the mRNA level in relevant dorsal root ganglia was determined by reverse transcription polymerase chain reaction using rat-specific primers. Nociceptive and non-nociceptive mechanoreceptor neurons exhibiting changes in neural firing patterns associated with increased nociception due to the presence of a bone tumour rapidly responded to sulphasalazine injection, an agent that pharmacologically blocks non-vesicular glutamate release by inhibiting the activity of the system x C À antiporter. In addition, both types of mechanoreceptor neurons demonstrated excitation in response to intramuscular glutamate injection near the femoral head, which corresponds to the location of cancer cell injection to induce the bone cancer-induced pain model. Therefore, glutamatergic signalling contributes to cancer pain and may be a factor in peripheral sensitization and induced tactile hypersensitivity associated with bone cancer-induced pain.

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Section: Discussionmentioning

confidence: 99%

Bone cancer-induced pain is associated with glutamate signalling in peripheral sensory neurons

Zhu

Linher‐Melville

et al. 2020

Mol Pain

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“…However, there are at least three possible mechanisms that may be driving this skin hypersensitivity. The first and probably most well investigated mechanism is that skeletal pain is highly efficacious in driving central sensitization and in turn may affect signaling to and from higher centers of the brain resulting in changes to descending modulation and ascending facilitation of pain signaling [18; 26; 63–65; 68]. …”

Section: Discussionmentioning

confidence: 99%

Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain

Guedon

Longo

Majuta

et al. 2016

Pain

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Recent studies have suggested that in humans and animals with significant skeletal pain, changes in the mechanical hypersensitivity of the skin can be detected. However, whether measuring changes in skin hypersensitivity can be a reliable surrogate for measuring skeletal pain itself remains unclear. To explore this question we generated skeletal pain by injecting and confining GFP-transfected NCTC 2472 osteosarcoma cells unilaterally to the femur of C3H male mice. Beginning at day 7 post-tumor injection, animals were administered vehicle, an antibody to the P2X3 receptor (anti-P2X3) or anti-NGF antibody. Pain and analgesic efficacy was then measured on days 21, 28 and 35 post-tumor injection using a battery of skeletal pain-related behaviors and von Frey assessment of mechanical hypersensitivity on the plantar surface of the hindpaw. Animals with bone cancer pain treated with anti-P2X3 showed a reduction in skin hypersensitivity but no attenuation of skeletal pain behaviors. Whereas animals with bone cancer pain treated with anti-NGF showed a reduction in both skin hypersensitivity and skeletal pain behaviors. These results suggest that while bone cancer can induce significant skeletal pain-related behaviors and hypersensitivity of the skin, relief of hypersensitivity of the skin is not always accompanied by attenuation of skeletal pain. Understanding the relationship between skeletal and skin pain may provide insight into how pain is processed and integrated and help define the preclinical measures of skeletal pain that are predictive endpoints for clinical trials.

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“…Aditi Gupta et al reported that, the expression of RANKL could be knocked down by phosphorylation of Smad5 suppression, therefore reducing osteoclast differentiation and consequently lessening bone loss and BCP [36]. We also learned that activation of PI3Kγ/Akt pathway, downstream of miR-93, could activate spinal microglia through MCP-1 and mediates BCP [37, 38]. Taken together, miR-93/Smad5 is suggested as an important mediator in BCP.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-93-5p may participate in the formation of morphine tolerance in bone cancer pain mouse model by targeting Smad5

Xiao

Lou

et al. 2016

Oncotarget

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ObjectiveIn this study, we aim to find out the role of microRNA-93-5p (miR-93) and Smad5 in morphine tolerance in mouse models of bone cancer pain (BCP).ResultsAt 7 days after injection of morphine, the PMWT showed no significant difference between the morphine model group and the saline model group (P < 0.05), suggesting that morphine tolerance had formed in the morphine model group. The morphine model group had higher miR-93 expression and lower Smad5 mRNA expression than the saline model group. Smad5 is a downstream target gene of miR-93. At 7, 9 and 14 days after injection of lentiviruses, the L/anti-miR-93 group had the lowest PMWTs, while the Smad5 shRNA group presented the highest PMWTs among these five groups (all P < 0.05).MethodsWe built mouse models of BCP and morphine tolerance and recorded 50% PMWT. After 6 days of modeling, we set saline control group, morphine control, saline model group and morphine model group (morphine tolerance emerged). We performed luciferase reporter gene assay to verify the relation between miR-93 and Smad5. After lentivirus transfection, the mice with morphine tolerance were assigned into L/anti-miR-93 group, Smad5 shRNA group, L/anti-miR-93 + Smad5 shRNA group, blank group and PBS control group. RT-qPCR, Western Blot assay and immumohistochemical staining were performed to observe the changes of miR-93 and Smad5.ConclusionUp-regulation of miR-93 may contribute to the progression of morphine tolerance by targeting Smad5 in mouse model of BCP.

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Activation of PI3Kγ/Akt pathway mediates bone cancer pain in rats

Cited by 37 publications

References 47 publications

Bone cancer-induced pain is associated with glutamate signalling in peripheral sensory neurons

Bone cancer-induced pain is associated with glutamate signalling in peripheral sensory neurons

Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain

MicroRNA-93-5p may participate in the formation of morphine tolerance in bone cancer pain mouse model by targeting Smad5

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