ω-Conotoxin inhibition of excitatory synaptic transmission evoked by dorsal root stimulation in rat superficial dorsal horn

Motin, Leonid; Adams, David J.

doi:10.1016/j.neuropharm.2008.06.049

Cited by 27 publications

(39 citation statements)

References 20 publications

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“…The spinal cord was isolated from 8-to 15-day-old Wistar rats as described previously (Motin and Adams, 2008). Before experiments, slices were kept in artificial cerebrospinal fluid for 1 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Upon formation of whole-cell recording configuration, neurons were first held in current-clamp configuration to evaluate their resting membrane potential and responses to depolarizing current injections. Excitatory postsynaptic currents (EPSCs) were recorded under voltage-clamp conditions from a holding potential of Ϫ80 mV in the presence of 100 M picrotoxin and 10 M strychnine to block inhibitory synaptic transmission and were categorized as monosynaptic or polysynaptic responses as described previously (Motin and Adams, 2008). EPSC amplitude was monitored online using Clampex 9.2 software package.…”

Section: Methodsmentioning

confidence: 99%

“…CVID, MVIIA, and GVIA also cause irreversible inhibition of synaptic transmission between primary afferents and superficial dorsal horn neurons of rats (Motin and Adams, 2008). On the other hand, the block by -conotoxin CVIB, an antagonist of both N-and P/Q-type VGCCs, has been shown recently to reversibly inhibit excitatory synaptic transmission in the spinal cord (Motin and Adams, 2008). Recovery from block may influence how effectively -conotoxins reverse different painful conditions in vivo, and could indicate whether administration of these peptides can be controlled to avoid unwanted side effects (Wright et al, 2000).…”

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confidence: 98%

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confidence: 99%

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Analgesic ω-Conotoxins CVIE and CVIF Selectively and Voltage-Dependently Block Recombinant and Native N-Type Calcium Channels

Berecki

Motin²,

Haythornthwaite³

et al. 2009

Mol Pharmacol

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Neuronal (N)-type Ca2ϩ channel-selective -conotoxins have emerged as potential new drugs for the treatment of chronic pain. In this study, two new -conotoxins, CVIE and CVIF, were discovered from a Conus catus cDNA library. Both conopeptides potently displaced 125 I-GVIA binding to rat brain membranes. In Xenopus laevis oocytes, CVIE and CVIF potently and selectively inhibited depolarizationactivated Ba 2ϩ currents through recombinant N-type (␣1 B-b / ␣ 2 ␦1/␤ 3 ) Ca 2ϩ channels. Recovery from block increased with membrane hyperpolarization, indicating that CVIE and CVIF have a higher affinity for channels in the inactivated state. The link between inactivation and the reversibility of -conotoxin action was investigated by creating molecular diversity in ␤ subunits: N-type channels with ␤ 2a subunits almost completely recovered from CVIE or CVIF block, whereas those with ␤ 3 subunits exhibited weak recovery, suggesting that reversibility of the -conotoxin block may depend on the type of ␤-subunit isoform. In rat dorsal root ganglion sensory neurons, neither peptide had an effect on low-voltageactivated T-type channels but potently and selectively inhibited high voltage-activated N-type Ca 2ϩ channels in a voltage-dependent manner. In rat spinal cord slices, both peptides reversibly inhibited excitatory monosynaptic transmission between primary afferents and dorsal horn superficial lamina neurons. Homology models of CVIE and CVIF suggest that -conotoxin/voltage-gated Ca 2ϩ channel interaction is dominated by ionic/electrostatic interactions. In the rat partial sciatic nerve ligation model of neuropathic pain, CVIE and CVIF (1 nM) significantly reduced allodynic behavior. These N-type Ca 2ϩ channel-selective -conotoxins are therefore useful as neurophysiological tools and as potential therapeutic agents to inhibit nociceptive pain pathways.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

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Analgesic ω-Conotoxins CVIE and CVIF Selectively and Voltage-Dependently Block Recombinant and Native N-Type Calcium Channels

Berecki

Motin²,

Haythornthwaite³

et al. 2009

Mol Pharmacol

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show abstract

“…4). P/Q-type VDCC blockers contribute less than N-type VDCCs to the voltage-gated Ca 2+ current in the DRG (39) and have no effect on the input from primary afferent fibers into dorsal horn neurons (5,34). Although both N-and P/Q-type VDCCs are expressed in the spinal cord, P/Q-type VDCCs are localized primarily in interneurons (15).…”

Section: Figmentioning

confidence: 99%

N- and L-Type Voltage-Dependent Ca<SUP>2+</SUP> Channels Contribute to the Generation of After-Discharges in the Spinal Ventral Root After Cessation of Noxious Mechanical Stimulation

2012

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Abstract. Voltage-dependent Ca2+ channels (VDCCs) play a crucial role in the spinal pain transduction. We previously reported that nociceptive mechanical stimuli to the rat hindpaw evoked two types of ventral root discharges that increased during stimulation (during-discharges) and after cessation of stimulation (after-discharges). To explore the involvement of VDCCs in these ventral root discharges, several VDCC blockers were applied directly to the surface of the spinal cord. Spinalized rats were laminectomized. The fifth lumbar ventral root was sectioned and used for multi-unit efferent discharges recording. An agar pool was constructed on the first lumbar vertebra for drug application. Ethosuximide (a T-type VDCC blocker) had no effect on ventral root discharges. ω-Conotoxin GVIA (an N-type VDCC blocker) preferentially suppressed after-discharges. ω-Agatoxin IVA (a P/Q-type VDCC blocker), diltiazem, and verapamil (L-type VDCC blockers) nonselectively depressed both during-and after-discharges. The more selective L-type VDCC blocker nicardipine depressed only after-discharges and the depression was exhibited when nicardipine was microinjected into the dorsal horn, but not into the ventral horn. These findings suggested that N-and L-type VDCCs in the dorsal horn were involved in the generation of afterdischarges and these blockers might be useful for treatment of persistent pain that involves the spinal pathway.

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Voltage‐Gated Calcium Channels as Targets for the Treatment of Chronic Pain

McGivern

2009

Peripheral Receptor Targets for Analgesia

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ω-Conotoxin inhibition of excitatory synaptic transmission evoked by dorsal root stimulation in rat superficial dorsal horn

Cited by 27 publications

References 20 publications

Analgesic ω-Conotoxins CVIE and CVIF Selectively and Voltage-Dependently Block Recombinant and Native N-Type Calcium Channels

Analgesic ω-Conotoxins CVIE and CVIF Selectively and Voltage-Dependently Block Recombinant and Native N-Type Calcium Channels

N- and L-Type Voltage-Dependent Ca<SUP>2+</SUP> Channels Contribute to the Generation of After-Discharges in the Spinal Ventral Root After Cessation of Noxious Mechanical Stimulation

Voltage‐Gated Calcium Channels as Targets for the Treatment of Chronic Pain

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