Effect of down—regulation of voltage—gated sodium channel Nav1.7 on activation of astrocytes and microglia in DRG in rats with cancer pain

Pan, Jun; Lin, Xiaoyan; Ling, Zhi-Heng; Cai, Youzhi

doi:10.1016/s1995-7645(14)60352-7

Cited by 16 publications

(19 citation statements)

References 22 publications

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“…Injection of these cells in the bones sequentially activates the extracellular signal-regulated protein kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway in various cell types in the spinal cord of rats (Wang et al, 2011; Wang X. W. et al, 2012b; Bian et al, 2016). Sodium channels expressed by sensory nerve fibers including voltage gated sodium ion channels (Na v )1.7, Na v 1.8, and Na v 1.9 (Miao et al, 2010; Qiu et al, 2012; Pan J. et al, 2015) as well as potassium ion channels, high-voltage-activated calcium channels, hyperpolarization-activated cation channels, transient receptor potential cation channel subfamily V member 1 (TRPV1) (Duan et al, 2012; Xu et al, 2013; Xia et al, 2014), and acid-sensing ion channel 3 (Qiu et al, 2014) may also be important determinants of enhanced neuronal excitability in this breast CIBP model in rats.…”

Section: Targets For Novel Analgesic Drug Discoverymentioning

confidence: 99%

The Walker 256 Breast Cancer Cell- Induced Bone Pain Model in Rats

et al. 2016

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The majority of patients with terminal breast cancer show signs of bone metastasis, the most common cause of pain in cancer. Clinically available drug treatment options for the relief of cancer-associated bone pain are limited due to either inadequate pain relief and/or dose-limiting side-effects. One of the major hurdles in understanding the mechanism by which breast cancer causes pain after metastasis to the bones is the lack of suitable preclinical models. Until the late twentieth century, all animal models of cancer induced bone pain involved systemic injection of cancer cells into animals, which caused severe deterioration of animal health due to widespread metastasis. In this mini-review we have discussed details of a recently developed and highly efficient preclinical model of breast cancer induced bone pain: Walker 256 cancer cell- induced bone pain in rats. The model involves direct localized injection of cancer cells into a single tibia in rats, which avoids widespread metastasis of cancer cells and hence animals maintain good health throughout the experimental period. This model closely mimics the human pathophysiology of breast cancer induced bone pain and has great potential to aid in the process of drug discovery for treating this intractable pain condition.

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Section: Targets For Novel Analgesic Drug Discoverymentioning

confidence: 99%

The Walker 256 Breast Cancer Cell- Induced Bone Pain Model in Rats

et al. 2016

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“…As a key member of the VGSC family, Na v 1.7 is widely expressed in DRG cell membranes and involved in maintenance and transfer of cell excitability. 16,17 Inhibition of Na v 1.7 also reduces the activation of astrocytes and microglia in DRG. 15 Downregulation of Na v 1.7 can reduce the expression of GFAP and OX42 in DRG in rats with cancer pain and in a rat model of morphine-tolerant bone cancer pain.…”

Section: Discussionmentioning

confidence: 99%

“…14 Na v 1.7 is widely expressed in the cell membrane of DRG, sympathetic neurons, and Schwann cells, and it plays a key role in the maintenance and transfer of cell excitability. 16,17 In addition, downregulation of Na v l.7 can reduce expression of glial fibrillary acidic protein (GFAP), a hallmark of satellite glial cell (SGC) and SGC activation in DRG, indicating a crucial role of Na v 1.7 in regulating glia activation in DRG. 15 Na v 1.7 inhibition prevents pain by blocking activation of neuroglia; therefore, Na v 1.7 blockers are used in local and general anesthetics.…”

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confidence: 99%

“…14 A recent study confirms that Na v 1.7 is involved in pain related to cancer, inflammation, and neuropathy. 17 CFA is frequently used to induce chronic inflammatory pain. 16,17 In addition, downregulation of Na v l.7 can reduce expression of glial fibrillary acidic protein (GFAP), a hallmark of satellite glial cell (SGC) and SGC activation in DRG, indicating a crucial role of Na v 1.7 in regulating glia activation in DRG.…”

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confidence: 99%

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Inhibition of lncRNA X inactivate‐specific transcript ameliorates inflammatory pain by suppressing satellite glial cell activation and inflammation by acting as a sponge of miR‐146a to inhibit Na_v1.7

Sun

et al. 2018

J of Cellular Biochemistry

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Long noncoding RNAs (lncRNA) has been validated to participate in nociception in inflammatory pain, presenting as a potential target against anesthesia. Previous research work confirmed the correlation between lncRNA X inactivate-specific transcript (XIST) and inflammation. However, its role in inflammatory pain is undefined. In animal pain models, voltage-gated sodium channels (VGSCs) reportedly participate in neural excitation. In this study, we observed the high expression of XIST and VGSC 1.7 (Na 1.7) in the dorsal root ganglion (DRG) of the complete Freund's adjuvant (CFA)-induced rat inflammatory pain model. Furthermore, XIST inhibition alleviated pain behavior and the activation of DRG satellite glial cells by suppressing glial fibrillary acidic protein (GFAP) expression, as well as inflammatory cytokine levels of interleukin-6 and tumor necrosis factor-α. XIST downregulation increased the mechanical pain threshold in an inflammatory pain model. Moreover, the expression of miR-146a was decreased in CFA rats. In vitro, XIST acted as a sponge of miR-146a, which targeted Na 1.7 via bioinformatic prediction, luciferase reporter, and pull-down assay. More importantly, activation of the Na 1.7 pathway or miR-146 depression both reversed XIST knockdown-inhibited satellite glial cell activation and inflammatory pain in CFA rats. These results suggest that cessation of XIST may ameliorate inflammatory pain by acting as a sponge of miR-146a to inhibit Nav1.7, implying a promising strategy against inflammatory pain.

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“…As noted above, Na v 1.3 expression increases with nerve injury. Intrathecal knockdown of these channels with antisense reduced their upregulation in nerve injury and reduced the behaviorally defined tactile allodynia [147][148][149]. The use of intrathecally-delivered siRNA and antisense targeting these structures clearly offers a direct approach to targeting these membrane proteins [127,130,131].…”

Section: Future Directions For Spinal Sodium Channel Blockersmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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Effect of down—regulation of voltage—gated sodium channel Nav1.7 on activation of astrocytes and microglia in DRG in rats with cancer pain

Abstract: Intrathecal injection of Navl.7 shRNA lentiviral vector can reduce the expression of Nav1.7 and inhibit the activation of astrocytes and microglia in DRG. The effort is also effective in morphine tolerance bone cancer pain model rats.

Cited by 16 publications

References 22 publications

The Walker 256 Breast Cancer Cell- Induced Bone Pain Model in Rats

The Walker 256 Breast Cancer Cell- Induced Bone Pain Model in Rats

Inhibition of lncRNA X inactivate‐specific transcript ameliorates inflammatory pain by suppressing satellite glial cell activation and inflammation by acting as a sponge of miR‐146a to inhibit Na_v1.7

Current and Future Issues in the development of spinal agents for the management of pain

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Effect of down—regulation of voltage—gated sodium channel Nav1.7 on activation of astrocytes and microglia in DRG in rats with cancer pain

Abstract: Intrathecal injection of Navl.7 shRNA lentiviral vector can reduce the expression of Nav1.7 and inhibit the activation of astrocytes and microglia in DRG. The effort is also effective in morphine tolerance bone cancer pain model rats.

Cited by 16 publications

References 22 publications

The Walker 256 Breast Cancer Cell- Induced Bone Pain Model in Rats

The Walker 256 Breast Cancer Cell- Induced Bone Pain Model in Rats

Inhibition of lncRNA X inactivate‐specific transcript ameliorates inflammatory pain by suppressing satellite glial cell activation and inflammation by acting as a sponge of miR‐146a to inhibit Nav1.7

Current and Future Issues in the development of spinal agents for the management of pain

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Inhibition of lncRNA X inactivate‐specific transcript ameliorates inflammatory pain by suppressing satellite glial cell activation and inflammation by acting as a sponge of miR‐146a to inhibit Na_v1.7