Category: Dorsal Root Ganglion Block

Hyperinsulinemia Induces Insulin Resistance in Dorsal Root Ganglion Neurons.

Hyperinsulinemia Induces Insulin Resistance in Dorsal Root Ganglion Neurons.

Endocrinology. 2011 Aug 2;

Authors: Kim B, McLean LL, Philip SS, Feldman EL

Insulin resistance (IR) is the major feature of metabolic syndrome, including type 2 diabetes. IR studies are mainly focused on peripheral tissues, such as muscle and liver. There is, however, little knowledge about IR in neurons. In this study, we examined whether neurons develop IR in response to hyperinsulinemia. We first examined insulin signaling using adult dorsal root ganglion neurons as a model system. Acute insulin treatment resulted in time- and concentration-dependent activation of the signaling cascade, including phosphorylation of the insulin receptor, Akt, p70S6K, and glycogen synthase kinase-3?. To mimic hyperinsulinemia, cells were pretreated with 20 nm insulin for 24 h and then stimulated with 20 nm insulin for 15 min. Chronic insulin treatment resulted in increased basal Akt phosphorylation. More importantly, acute insulin stimulation after chronic insulin treatment resulted in blunted phosphorylation of Akt, p70S6K, and glycogen synthase kinase-3?. Interestingly, when the cells were treated with phosphatidylinositol 3-kinase pathway inhibitor, but not MAPK pathway inhibitor, chronic insulin treatment did not block acute insulin treatment-induced Akt phosphorylation. Insulin-induced Akt phosphorylation was lower in dorsal root ganglion neurons from BKS-db/db compared with control BKS-db+ mice. This effect was age dependent. Our results suggest that hyperinsulinemia cause IR by disrupting the Akt-mediated pathway. We also demonstrate that hyperinsulinemia increases the mitochondrial fission protein dynamin-related protein 1. Our results suggest a new theory for the etiology of diabetic neuropathy, i.e. that, similar to insulin dependent tissues, neurons develop IR and, in turn, cannot respond to the neurotrophic properties of insulin, resulting in neuronal injury and the development of neuropathy.

PMID: 21810948 [PubMed – as supplied by publisher]

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Effects of ranolazine on wild-type and mutant hNav1.7 channels and on DRG neuron excitability.

Effects of ranolazine on wild-type and mutant hNav1.7 channels and on DRG neuron excitability.

Mol Pain. 2010;6:35

Authors: Estacion M, Waxman SG, Dib-Hajj SD

A direct role of sodium channels in pain has recently been confirmed by establishing a monogenic link between SCN9A, the gene which encodes sodium channel Nav1.7, and pain disorders in humans, with gain-of-function mutations causing severe pain syndromes, and loss-of-function mutations causing congenital indifference to pain. Expression of sodium channel Nav1.8 in DRG neurons has also been shown to be essential for the manifestation of mutant Nav1.7-induced neuronal hyperexcitability. These findings have confirmed key roles of Nav1.7 and Nav1.8 in pain and identify these channels as novel targets for pain therapeutic development. Ranolazine preferentially blocks cardiac late sodium currents at concentrations that do not significantly reduce peak sodium current. Ranolazine also blocks wild-type Nav1.7 and Nav1.8 channels in a use-dependent manner. However, ranolazine’s effects on gain-of-function mutations of Nav1.7 and on DRG neuron excitability have not been investigated. We used voltage- and current-clamp recordings to evaluate the hypothesis that ranolazine may be effective in regulating Nav1.7-induced DRG neuron hyperexcitability.

PMID: 20529343 [PubMed – indexed for MEDLINE]

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CT-guided blocks and neuroablation of the ganglion impar (Walther) in perineal pain: anatomy, technique, safety, and efficacy.

CT-guided blocks and neuroablation of the ganglion impar (Walther) in perineal pain: anatomy, technique, safety, and efficacy.

Clin J Pain. 2009 Sep;25(7):570-6

Authors: Agarwal-Kozlowski K, Lorke DE, Habermann CR, Am Esch JS, Beck H

An alternate approach to the ganglion impar was chosen to minimize the risk of adverse events. Efficacy of the procedure was evaluated.

PMID: 19692797 [PubMed – indexed for MEDLINE]

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Sensory neurons and schwann cells respond to oxidative stress by increasing antioxidant defense mechanisms.

Sensory neurons and schwann cells respond to oxidative stress by increasing antioxidant defense mechanisms.

Antioxid Redox Signal. 2009 Mar;11(3):425-38

Authors: Vincent AM, Kato K, McLean LL, Soules ME, Feldman EL

Elevated blood glucose is a key initiator of mechanisms leading to diabetic neuropathy. Increases in glucose induce acute mitochondrial oxidative stress in dorsal root ganglion (DRG) neurons, the sensory neurons normally affected in diabetic neuropathy, whereas Schwann cells are largely unaffected. We propose that activation of an antioxidant response in DRG neurons would prevent glucose-induced injury. In this study, mild oxidative stress (1 microM H2O2) leads to the activation of the transcription factor Nrf2 and expression of antioxidant (phase II) enzymes. DRG neurons are thus protected from subsequent hyperglycemia-induced injury, as determined by activation of caspase 3 and the TUNEL assay. Schwann cells display high basal antioxidant enzyme expression and respond to hyperglycemia and mild oxidative stress via further increases in these enzymes. The botanical compounds resveratrol and sulforaphane activate the antioxidant response in DRG neurons. Other drugs that protect DRG neurons and block mitochondrial superoxide, identified in a compound screen, have differential ability to activate the antioxidant response. Multiple cellular targets exist for the prevention of hyperglycemic oxidative stress in DRG neurons, and these form the basis for new therapeutic strategies against diabetic neuropathy.

PMID: 19072199 [PubMed – indexed for MEDLINE]

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Pain relief after cervical ganglionectomy (C2 and C3) for the treatment of medically intractable occipital neuralgia.

Pain relief after cervical ganglionectomy (C2 and C3) for the treatment of medically intractable occipital neuralgia.

Stereotact Funct Neurosurg. 2008;86(2):106-12

Authors: Acar F, Miller J, Golshani KJ, Israel ZH, McCartney S, Burchiel KJ

Occipital neuralgia (ON) presents a diagnostic challenge because of the wide variety of symptoms, surgical findings, and postsurgical outcomes. Surgical removal of the second (C2) or third (C3) cervical sensory dorsal root ganglion is an option to treat ON. The goal of this study was to evaluate the short-term and the long-term efficacy of these procedures for management of cervical and occipital neuropathic pain. Twenty patients (mean age 48.7 years) were identified who had undergone C2 and/or C3 ganglionectomies for intractable occipital pain and a retrospective chart review undertaken. Patients were interviewed regarding pain relief, pain relief duration, functional status, medication usage and procedure satisfaction, preoperatively, immediately postoperative, and at follow-up (mean 42.5 months). C2, C3 and consecutive ganglionectomies at both levels were performed on 4, 5, and 11 patients, respectively. All patients reported preoperative pain relief following cervical nerve blocks. Average visual analog scale scores were 9.4 preoperatively and 2.6 immediately after procedure. Ninety-five percent of patients reported short-term pain relief (<3 months). In 13 patients (65%), pain returned after an average of 12 months (C2 ganglionectomy) and 8.4 months (C3 ganglionectomy). Long-term results were excellent, moderate and poor in 20, 40 and 40% of patients, respectively. Cervical ganglionectomy offers relief to a majority of patients, immediately after procedure, but the effect is short lived. Nerve blocks are helpful in predicting short-term success, but a positive block result does not necessarily predict long-term benefit and therefore cannot justify surgery by itself. However, since 60% of patients report excellent-moderate results, cervical ganglionectomy continues to have a role in the treatment of intractable ON.

PMID: 18216457 [PubMed – indexed for MEDLINE]

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Immortalization and characterization of a nociceptive dorsal root ganglion sensory neuronal line.

Immortalization and characterization of a nociceptive dorsal root ganglion sensory neuronal line.

J Peripher Nerv Syst. 2007 Jun;12(2):121-30

Authors: Chen W, Mi R, Haughey N, Oz M, Höke A

Development of neuroprotective strategies for peripheral neuropathies requires high-throughput drug screening assays with appropriate cell types. Currently, immortalized dorsal root ganglion (DRG) sensory neuronal cell lines that maintain nociceptive sensory neuronal properties are not available. We generated immortalized DRG neuronal lines from embryonic day 14.5 rats. Here, we show that one of the immortalized DRG neuronal lines, 50B11, has the properties of a nociceptive neuron. When differentiated in the presence of forskolin, these cells extend long neurites, express neuronal markers, and generate action potentials. They express receptors and markers of small-diameter sensory neurons and upregulate appropriate receptor populations when grown in the presence of glial cell line-derived neurotrophic factor or nerve growth factor. Furthermore, they express capsaicin receptor transient receptor potential vanilloid family-1 (TRPV-1) and respond to capsaicin with increases in intracellular calcium. In a 96-well plate format, these neurons show a decline in ATP levels when exposed to dideoxycytosine (ddC) in a proper time- and dose-dependent manner. This ddC-induced reduction in ATP levels correlates with axonal degeneration. The immortalized DRG neuronal cell line 50B11 can be used for high-throughput drug screening for neuroprotective agents for axonal degeneration and antinociceptive drugs that block TRPV-1.

PMID: 17565537 [PubMed – indexed for MEDLINE]

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Identification of ML204: a novel potent antagonist that selectively modulates native TRPC4/C5 channels.

Identification of ML204: a novel potent antagonist that selectively modulates native TRPC4/C5 channels.

J Biol Chem. 2011 Jul 27;

Authors: Miller M, Shi J, Zhu Y, Kustov M, Tian JB, Stevens A, Wu M, Xu J, Long S, Yang P, Zholos AV, Salovich JM, Weaver CD, Hopkins CR, Lindsley CW, McManus O, Li M, Zhu MX

Transient receptor potential canonical (TRPC) channels are Ca2+-permeable nonselective cation channels implicated in diverse physiological functions, including smooth muscle contractility and synaptic transmission. However, lack of potent selective pharmacological inhibitors for TRPC channels has limited delineation of the roles of these channels in physiological systems. Here we report the identification and characterization of ML204 as a novel, potent and selective TRPC4 channel inhibitor. A high-throughput fluorescent screen of 305,000 compounds of the Molecular Libraries Small Molecule Repository (MLSMR) was performed for inhibitors that blocked intracellular Ca2+ rise in response to stimulation of mouse TRPC4beta by mu-opioid receptors. ML204 inhibited TRPC4beta-mediated intracellular Ca2+ rise with an IC50 value of 0.96 uM and exhibited 19-fold selectivity against muscarinic receptor-coupled TRPC6 channel activation. In whole-cell patch clamp recordings, ML204 blocked TRPC4beta currents activated through either mu-opioid receptor stimulation or intracellular dialysis of GTP(gamma)S suggesting a direct interaction of ML204 with TRPC4 channels rather than any interference with the signal transduction pathways. Selectivity studies showed no appreciable block by 10-20 uM of ML204 of TRPV1, TRPV3, TRPA1, and TRPM8, as well as KCNQ2 and native voltage-gated sodium, potassium, and calcium channels in mouse dorsal root ganglion neurons. In isolated guinea pig ileal myocytes, ML204 blocked muscarinic cation currents activated by bath application of carbachol or intracellular infusion of GTP(gamma)S, demonstrating its effectiveness on native TRPC4 currents. Therefore, ML204 represents an excellent novel tool for investigation of TRPC4 channel function and may facilitate the development of therapeutics targeted to TRPC4.

PMID: 21795696 [PubMed – as supplied by publisher]

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Analgesic effects of a substituted N-triazole oxindole (TROX-1), a state-dependent, voltage-gated calcium channel 2 blocker.

Analgesic effects of a substituted N-triazole oxindole (TROX-1), a state-dependent, voltage-gated calcium channel 2 blocker.

J Pharmacol Exp Ther. 2010 Aug;334(2):545-55

Authors: Abbadie C, McManus OB, Sun SY, Bugianesi RM, Dai G, Haedo RJ, Herrington JB, Kaczorowski GJ, Smith MM, Swensen AM, Warren VA, Williams B, Arneric SP, Eduljee C, Snutch TP, Tringham EW, Jochnowitz N, Liang A, Euan MacIntyre D, McGowan E, Mistry S, White VV, Hoyt SB, London C, Lyons KA, Bunting PB, Volksdorf S, Duffy JL

Voltage-gated calcium channel (Ca(v))2.2 (N-type calcium channels) are key components in nociceptive transmission pathways. Ziconotide, a state-independent peptide inhibitor of Ca(v)2.2 channels, is efficacious in treating refractory pain but exhibits a narrow therapeutic window and must be administered intrathecally. We have discovered an N-triazole oxindole, (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1), as a small-molecule, state-dependent blocker of Ca(v)2 channels, and we investigated the therapeutic advantages of this compound for analgesia. TROX-1 preferentially inhibited potassium-triggered calcium influx through recombinant Ca(v)2.2 channels under depolarized conditions (IC(50) = 0.27 microM) compared with hyperpolarized conditions (IC(50) > 20 microM). In rat dorsal root ganglion (DRG) neurons, TROX-1 inhibited omega-conotoxin GVIA-sensitive calcium currents (Ca(v)2.2 channel currents), with greater potency under depolarized conditions (IC(50) = 0.4 microM) than under hyperpolarized conditions (IC(50) = 2.6 microM), indicating state-dependent Ca(v)2.2 channel block of native as well as recombinant channels. TROX-1 fully blocked calcium influx mediated by a mixture of Ca(v)2 channels in calcium imaging experiments in rat DRG neurons, indicating additional block of all Ca(v)2 family channels. TROX-1 reversed inflammatory-induced hyperalgesia with maximal effects equivalent to nonsteroidal anti-inflammatory drugs, and it reversed nerve injury-induced allodynia to the same extent as pregabalin and duloxetine. In contrast, no significant reversal of hyperalgesia was observed in Ca(v)2.2 gene-deleted mice. Mild impairment of motor function in the Rotarod test and cardiovascular functions were observed at 20- to 40-fold higher plasma concentrations than required for analgesic activities. TROX-1 demonstrates that an orally available state-dependent Ca(v)2 channel blocker may achieve a therapeutic window suitable for the treatment of chronic pain.

PMID: 20439438 [PubMed – indexed for MEDLINE]

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Isoflurane inhibits the tetrodotoxin-resistant voltage-gated sodium channel Nav1.8.

Isoflurane inhibits the tetrodotoxin-resistant voltage-gated sodium channel Nav1.8.

Anesthesiology. 2009 Sep;111(3):591-9

Authors: Herold KF, Nau C, Ouyang W, Hemmings HC

Voltage-gated sodium channels (Nav) mediate neuronal action potentials. Tetrodotoxin inhibits all Nav isoforms, but Nav1.8 and Nav1.9 are relatively tetrodotoxin-resistant (TTX-r) compared to other isoforms. Nav1.8 is highly expressed in dorsal root ganglion neurons and is functionally linked to nociception, but the sensitivity of TTX-r isoforms to inhaled anesthetics is unclear.

PMID: 19672182 [PubMed – indexed for MEDLINE]

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Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases.

Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases.

FASEB J. 2009 Apr;23(4):1102-14

Authors: Bessac BF, Sivula M, von Hehn CA, Caceres AI, Escalera J, Jordt SE

The release of methyl isocyanate in Bhopal, India, caused the worst industrial accident in history. Exposures to industrial isocyanates induce lacrimation, pain, airway irritation, and edema. Similar responses are elicited by chemicals used as tear gases. Despite frequent exposures, the biological targets of isocyanates and tear gases in vivo have not been identified, precluding the development of effective countermeasures. We use Ca(2+) imaging and electrophysiology to show that the noxious effects of isocyanates and those of all major tear gas agents are caused by activation of Ca(2+) influx and membrane currents in mustard oil-sensitive sensory neurons. These responses are mediated by transient receptor potential ankyrin 1 (TRPA1), an ion channel serving as a detector for reactive chemicals. In mice, genetic ablation or pharmacological inhibition of TRPA1 dramatically reduces isocyanate- and tear gas-induced nocifensive behavior after both ocular and cutaneous exposures. We conclude that isocyanates and tear gas agents target the same neuronal receptor, TRPA1. Treatment with TRPA1 antagonists may prevent and alleviate chemical irritation of the eyes, skin, and airways and reduce the adverse health effects of exposures to a wide range of toxic noxious chemicals.

PMID: 19036859 [PubMed – indexed for MEDLINE]

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