Spinal administration of mGluR5 antagonist prevents the onset of bortezomib induced neuropathic pain in rat

Ghelardini, Carla; Menicacci, Cristina; Cerretani, Daniela; Bianchi, Enrica

doi:10.1016/j.neuropharm.2014.08.004

Cited by 21 publications

(13 citation statements)

References 47 publications

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“…However, these studies did not determine the effect of an intrathecal injection of rapamycin on the activity of DRG mTOR under chronic conditions. Our results show that the intrathecal administration of rapamycin has an effect on DRG mTOR, which is reported by other researchers [29], and a possible explanation for this phenomenon is that the duration of our treatment is longer than the duration of other treatments, and the drug targets DRGs at a mean of axoplasmic transport;…”

Section: Discussionsupporting

confidence: 85%

Intrathecal administration of rapamycin inhibits the phosphorylation of DRG Nav1.8 and attenuates STZ-induced painful diabetic neuropathy in rats

Zhang

Xiong

et al. 2016

Neuroscience Letters

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The mammalian target of rapamycin (mTOR) is a key regulator of mRNA translation and protein synthesis, and it is specifically inhibited by rapamycin. In chronic pain conditions, mTOR-mediated local protein synthesis is crucial for neuronal hyperexcitability and synaptic plasticity. The tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 plays a major role in action potential initiation and propagation and cellular excitability in DRG (dorsal root ganglion) neurons. In this study, we investigated if mTOR modulates the phosphorylation of Nav1.8 that is associated with neuronal hyperexcitability and behavioral hypersensitivity in STZ-induced diabetic rats. Painful diabetic neuropathy (PDN) was induced in Sprague-Dawley rats by intraperitoneal injection with streptozotocin (STZ) at 60mg/kg. After the onset of PDN, the rats received daily intrathecal administrations of rapamycin (1μg, 3μg, or 10μg/day) for 7 days; other diabetic rats received the same volumes of dimethyl sulfoxide (DMSO). Herein, we demonstrate a marked increase in protein expression of total mTOR and phospho-mTOR (p-mTOR) together with the up-regulation of phosphor-Nav1.8 (p-Nav1.8) prior to the mechanical withdrawal threshold reaching a significant reduction in dorsal root ganglions (DRGs). Furthermore, the intrathecal administration of rapamycin, inhibiting the activity of mTOR, suppressed the phosphorylation of DRG Nav1.8, reduced the TTX-R current density, heightened the voltage threshold for activation and lowered the voltage threshold for inactivation and relieved mechanical hypersensitivity in diabetic rats. An intrathecal injection (i.t.) of rapamycin inhibited the phosphorylation and enhanced the functional availability of DRG Nav1.8 attenuated STZ-induced hyperalgesia. These results suggest that rapamycin is a potential therapeutic intervention for clinical PDN.

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Section: Discussionsupporting

confidence: 85%

Intrathecal administration of rapamycin inhibits the phosphorylation of DRG Nav1.8 and attenuates STZ-induced painful diabetic neuropathy in rats

Zhang

Xiong

et al. 2016

Neuroscience Letters

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“…Accordingly, bortezomib increases levels of various proinflammatory cytokines, such as TNF and IL-1β ( Liang et al, 2014 ), in plasma that gain access to the CNS ( Yarlagadda et al, 2009 ) and activate de novo biosynthesis to increase DH-S1P and S1P ( Snider et al, 2010 ; Maceyka and Spiegel, 2014 ). Alternatively, bortezomib-induced events in the DRG ( Carozzi et al, 2013 ) may provoke production of reactive oxygen and nitrogen species ( Duggett and Flatters, 2017 ) and release of glutamate ( Ghelardini et al, 2014 ) from presynaptic nerve endings that could activate glial sphingolipid metabolism ( Kim et al, 2012 ). The resulting increased S1PR1 signaling in astrocytes promotes their activation, migration, and ensuing release of inflammatory mediators ( Rothhammer et al, 2017 ) to reinforce neuroinflammation and drive the establishment and maintenance of the neuronal sensitization in the CNS.…”

Section: Resultsmentioning

confidence: 99%

Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain

Stockstill

Doyle

Yan

et al. 2018

Journal of Experimental Medicine

113

120

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“…Yet, others have shown that topical menthol produces analgesia in paclitaxel CIPN patients 179 and this has been supported in a recent proof-of-concept study. 180 Other receptors subtypes including A3 adenosine receptors, 181 5HT2A receptors, 182 183 sigma-1 receptors 76 and mGluR5 receptors 184 have been implicated in CIPN and could prove potential avenues for new treatments.…”

Section: Changes In Ion Channels In Cipnmentioning

confidence: 99%

Clinical and preclinical perspectives on Chemotherapy-Induced Peripheral Neuropathy (CIPN): a narrative review

Flatters

Dougherty

Colvin

2017

British Journal of Anaesthesia

275

246

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This review provides an update on the current clinical and preclinical understanding of chemotherapy induced peripheral neuropathy (CIPN). The overview of the clinical syndrome includes a review of its assessment, diagnosis and treatment. CIPN is caused by several widely-used chemotherapeutics including paclitaxel, oxaliplatin, bortezomib. Severe CIPN may require dose reduction, or cessation, of chemotherapy, impacting on patient survival. While CIPN often resolves after chemotherapy, around 30% of patients will have persistent problems, impacting on function and quality of life. Early assessment and diagnosis is important, and we discuss tools developed for this purpose. There are no effective strategies to prevent CIPN, with limited evidence of effective drugs for treating established CIPN. Duloxetine has moderate evidence, with extrapolation from other neuropathic pain states generally being used to direct treatment options for CIPN. The preclinical perspective includes a discussion on the development of clinically-relevant rodent models of CIPN and some of the potentially modifiable mechanisms that have been identified using these models. We focus on the role of mitochondrial dysfunction, oxidative stress, immune cells and changes in ion channels from summary of the latest literature in these areas. Many causal mechanisms of CIPN occur simultaneously and/or can reinforce each other. Thus, combination therapies may well be required for most effective management. More effective treatment of CIPN will require closer links between oncology and pain management clinical teams to ensure CIPN patients are effectively monitored. Furthermore, continued close collaboration between clinical and preclinical research will facilitate the development of novel treatments for CIPN.

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Spinal administration of mGluR5 antagonist prevents the onset of bortezomib induced neuropathic pain in rat

Cited by 21 publications

References 47 publications

Intrathecal administration of rapamycin inhibits the phosphorylation of DRG Nav1.8 and attenuates STZ-induced painful diabetic neuropathy in rats

Intrathecal administration of rapamycin inhibits the phosphorylation of DRG Nav1.8 and attenuates STZ-induced painful diabetic neuropathy in rats

Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain

Clinical and preclinical perspectives on Chemotherapy-Induced Peripheral Neuropathy (CIPN): a narrative review

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