Attenuation of ongoing neuropathic pain by peripheral acting opioid involves activation of central dopaminergic neurocircuitry

Vaidya, Shivani; Shantanu, P. A.; Tiwari, Vinod

doi:10.1016/j.neulet.2021.135751

Cited by 23 publications

(12 citation statements)

References 22 publications

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“…These data are in agreement with our previous results [ 4 ] and with the peripheral pro-nociceptive effect of VEGF-A demonstrated by Selvaraj and colleagues [ 6 ] after an intraplantar injection as well as with the VEGF-A increase in synovial fluid of subjects afflicted by osteoarticular pain [ 7 ]. Furthermore, in the peripheral nervous system, an anti-VEGF-A mAb treatment was found to alleviate neuropathic pain induced by the chronic constriction injury of the sciatic nerve [ 5 ], suggesting an active role of VEGF-A also in the peripheral sensitization mechanisms [ 63 ]. In our hands, both the selective VEGFR-1 agonist PlGF-2 and the selective VEGFR-2 agonist VEGF-E induced nociception after i.t.…”

Section: Discussionmentioning

confidence: 99%

VEGF-A/VEGFR-1 signalling and chemotherapy-induced neuropathic pain: therapeutic potential of a novel anti-VEGFR-1 monoclonal antibody

Micheli

Parisio

Lucarini

et al. 2021

J Exp Clin Cancer Res

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Background Neuropathic pain is a clinically relevant adverse effect of several anticancer drugs that markedly impairs patients’ quality of life and frequently leads to dose reduction or therapy discontinuation. The poor knowledge about the mechanisms involved in neuropathy development and pain chronicization, and the lack of effective therapies, make treatment of chemotherapy-induced neuropathic pain an unmet medical need. In this context, the vascular endothelial growth factor A (VEGF-A) has emerged as a candidate neuropathy hallmark and its decrease has been related to pain relief. In the present study, we have investigated the role of VEGF-A and its receptors, VEGFR-1 and VEGFR-2, in pain signalling and in chemotherapy-induced neuropathy establishment as well as the therapeutic potential of receptor blockade in the management of pain. Methods Behavioural and electrophysiological analyses were performed in an in vivo murine model, by using selective receptor agonists, blocking monoclonal antibodies or siRNA-mediated silencing of VEGF-A and VEGFRs. Expression of VEGF-A and VEGFR-1 in astrocytes and neurons was detected by immunofluorescence staining and confocal microscopy analysis. Results In mice, the intrathecal infusion of VEGF-A (VEGF165 isoforms) induced a dose-dependent noxious hypersensitivity and this effect was mediated by VEGFR-1. Consistently, electrophysiological studies indicated that VEGF-A strongly stimulated the spinal nociceptive neurons activity through VEGFR-1. In the dorsal horn of the spinal cord of animals affected by oxaliplatin-induced neuropathy, VEGF-A expression was increased in astrocytes while VEGFR-1 was mainly detected in neurons, suggesting a VEGF-A/VEGFR-1-mediated astrocyte-neuron cross-talk in neuropathic pain pathophysiology. Accordingly, the selective knockdown of astrocytic VEGF-A by intraspinal injection of shRNAmir blocked the development of oxaliplatin-induced neuropathic hyperalgesia and allodynia. Interestingly, both intrathecal and systemic administration of the novel anti-VEGFR-1 monoclonal antibody D16F7, endowed with anti-angiogenic and antitumor properties, reverted oxaliplatin-induced neuropathic pain. Besides, D16F7 effectively relieved hypersensitivity induced by other neurotoxic chemotherapeutic agents, such as paclitaxel and vincristine. Conclusions These data strongly support the role of the VEGF-A/VEGFR-1 system in mediating chemotherapy-induced neuropathic pain at the central nervous system level. Thus, treatment with the anti-VEGFR-1 mAb D16F7, besides exerting antitumor activity, might result in the additional advantage of attenuating neuropathic pain when combined with neurotoxic anticancer agents.

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Section: Discussionmentioning

confidence: 99%

VEGF-A/VEGFR-1 signalling and chemotherapy-induced neuropathic pain: therapeutic potential of a novel anti-VEGFR-1 monoclonal antibody

Micheli

Parisio

Lucarini

et al. 2021

J Exp Clin Cancer Res

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“…It is well known that LPS can stimulate an inflammatory response in C6 cells. A C6 cell model of LPS-induced neuritis has been widely as an in vitro model of depression [ 26 ]. Based on the above research, the aim of the present study was to determine whether SH2D5 gene methylation regulates LPS-induced inflammation of C6 cells and to elucidate the regulatory function and underlying mechanism of helicid on SH2D5 gene methylation.…”

Section: Introductionmentioning

confidence: 99%

[Retracted] Helicid Improves Lipopolysaccharide‐Induced Apoptosis of C6 Cells by Regulating SH2D5 DNA Methylation via the CytC/Caspase9/Caspase3 Signaling Pathway

Zhang

Wang

Zhang

et al. 2022

Contrast Media & Molecular Imaging

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DNA methylation is reportedly associated with stress responses and depression. Treatment with antidepressants can regulate DNA methylation and, subsequently, gene expression in the hippocampus. Hence, DNA methylation is a potential target for treatment of depression. Screening of high-throughput data of a rat model of chronic unpredictable mild stress revealed relatively low expression of SH2 domain-containing 5 (SH2D5). SH2D5 can be overexpressed by treatment with helicid. Therefore, in order to further explore the role of SH2D5 in depression and whether helicid mediates the DNA methylation of SH2D5 as a potential antidepressant role, SH2D5 was overexpressed in C6 cells as a lipopolysaccharides (LPS)-induced model of depression. The expression levels of Bax, Bcl-2, Bad, and Daxx, and changes to the CytC/caspase9/caspase3 signal pathway were detected by qRT-PCR and Western blot analyses. After treatment with helicid or silencing of SH2D5, the above indices were detected. The results showed that helicid regulated the CytC/caspase9/caspase3 signaling pathway and improved the apoptosis indices of C6 cells through the overexpression of SH2D5. Interestingly, silencing of SH2D5 reversed the effects of helicid on the above indices. Then, in order to study the underlying mechanism, the cells were administered to helicid or 5-aza-2′-deoxycytidine (5-AzaD) and expression of SH2D5 was detected by qRT-PCR and Western blot analyses, while to assess the DNA methylation level of SH2D5 using bisulfite sequencing/PCR. The results showed that SH2D5 was hypermethylated with low expression in LPS-induced C6 cells, which was reversed by helicid and 5-AzaD. These results suggest that helicid may affect the CytC/caspase9/caspase3 apoptosis signaling pathway and improve the apoptosis indices by mediating DNA methylation of SH2D5.

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“…Surgery, viral infection, chemotherapy or cancer can lead to NP, which can progress into chronic pain, that greatly affects patients' normal life. 1,[15][16][17] Therefore, it is a medical problem that needs to be urgently solved. In this experiment, the NP rat model was generated using the SNI method.…”

Section: Discussionmentioning

confidence: 99%

The κ-Opioid Receptor Agonist U50488H Ameliorates Neuropathic Pain Through the Ca2+/CaMKII/CREB Pathway in Rats

Zhang¹,

Lun²,

Du³

et al. 2022

JIR

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Objective: To observe the ameliorative effect of kappa opioid receptor (KOR) agonist on rats with neuropathic pain (NP) and investigate the mechanism of action of the calcium ion (Ca 2+ )/calcium/calmodulin-dependent protein kinase II (CaMKII)/cyclic AMP response element-binding protein (CREB) pathway. Methods: A total of 40 Sprague Dawley rats were randomly divided into four groups: shamoperation group (Sham group), NP model group (NP group), NP + KOR agonist U50488H group (NU group) and NP + specific CaMKII antagonist (KN93) + U50488H group (NKU group). The thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) of each group of rats were determined. ELISA was applied to examine the changes in inflammatory factors and oxidative stress factors, and the apoptotic rate in dorsal root ganglia was observed using TUNEL staining. Ca 2+ concentration, content of oxidative stress index ROS and the release of calcitonin gene-related peptide (CGRP) and N-methyl-D-aspartate receptor (NMDAR) in the dorsal root ganglia were measured by the immunofluorescence assay. Finally, Western blotting was performed to detect expression changes in the Ca 2+ /CaMKII/CREB pathway. Results:The KOR agonist U50488H could improve the values of TWL and MWT of NP the rats, inhibit inflammatory responses and relieve oxidative stress injury. Its mechanisms of action were associated with U50488H repression of Ca 2+ influx, reduction of CGRP and NMDAR releases in the dorsal root ganglia and decreases in CaMKII and CREB phosphorylations in NP rats. Conclusion:The KOR agonist ameliorates NP through suppressing the activity of the Ca 2+ /CaMKII/CREB pathway.

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Attenuation of ongoing neuropathic pain by peripheral acting opioid involves activation of central dopaminergic neurocircuitry

Cited by 23 publications

References 22 publications

VEGF-A/VEGFR-1 signalling and chemotherapy-induced neuropathic pain: therapeutic potential of a novel anti-VEGFR-1 monoclonal antibody

VEGF-A/VEGFR-1 signalling and chemotherapy-induced neuropathic pain: therapeutic potential of a novel anti-VEGFR-1 monoclonal antibody

[Retracted] Helicid Improves Lipopolysaccharide‐Induced Apoptosis of C6 Cells by Regulating SH2D5 DNA Methylation via the CytC/Caspase9/Caspase3 Signaling Pathway

The κ-Opioid Receptor Agonist U50488H Ameliorates Neuropathic Pain Through the Ca2+/CaMKII/CREB Pathway in Rats

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