Antinociceptive effects of intrathecally administered huwentoxin-I, a selective N-type calcium channel blocker, in the formalin test in conscious rats

Chen, Jiaqin; Zhang, Yong-Quen; Dai, Jie; Luo, Zhuo-Min; Liang, Songping

doi:10.1016/j.toxicon.2004.08.018

Cited by 33 publications

(16 citation statements)

References 24 publications

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“…57 However, whereas huwentoxin-I blocks N-type channels with high affinity (EC 50 ϭ 100 nM) and selectivity, at high doses in vivo it exhibits a significantly lower degree of the motor dysfunction and ataxia compared with that for Prialt.…”

Section: Can Prialt Be Improved Upon? the Case For Identifying Orallymentioning

confidence: 99%

Targeting chronic and neuropathic pain: The N-type calcium channel comes of age

2005

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Summary:The rapid entry of calcium into cells through activation of voltage-gated calcium channels directly affects membrane potential and contributes to electrical excitability, repetitive firing patterns, excitation-contraction coupling, and gene expression. At presynaptic nerve terminals, calcium entry is the initial trigger mediating the release of neurotransmitters via the calcium-dependent fusion of synaptic vesicles and involves interactions with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex of synaptic release proteins. Physiological factors or drugs that affect either presynaptic calcium channel activity or the efficacy of calcium-dependent vesicle fusion have dramatic consequences on synaptic transmission, including that mediating pain signaling. The Ntype calcium channel exhibits a number of characteristics that make it an attractive target for therapeutic intervention concerning chronic and neuropathic pain conditions. Within the past year, both U.S. and European regulatory agencies have approved the use of the cationic peptide Prialt for the treatment of intractable pain. Prialt is the first N-type calcium channel blocker approved for clinical use and represents the first new proven mechanism of action for chronic pain intervention in many years. The present review discusses the rationale behind targeting the N-type calcium channel, some of the limitations confronting the widespread clinical application of Prialt, and outlines possible strategies to improve upon Prialt's relatively narrow therapeutic window.

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Section: Can Prialt Be Improved Upon? the Case For Identifying Orallymentioning

confidence: 99%

Targeting chronic and neuropathic pain: The N-type calcium channel comes of age

2005

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“…53) Intrathecal w-conotoxin MVIIA at 1.0 mg/kg, however, caused whole body shaking and tail movement. 53) These data suggest that the safety profile of cilnidipine is better than that of ziconotide. The manner by which cilnidipine blocked N-type VDCC currents was different from that by w-conotoxin MVIIA as noted above 50,51) and may contribute to the better safety profile of cilnidipine.…”

Section: 237-41)mentioning

confidence: 99%

“…51) In contrast, ziconotide or w-conotoxin MVIIA, when injected intrathecally at higher doses that elicit marked antinociceptive effects, produces side-effects, including serpentine-like tail movement, whole body shaking, or allodynia. 4,5,33,52,53) For example, Chen et al showed that w-conotoxin MVIIA, when intrathecally injected at 0.1, 0.5, and 1.0 mg/kg, dose-dependently suppressed formalin-induced nociception in rats. 53) Intrathecal w-conotoxin MVIIA at 1.0 mg/kg, however, caused whole body shaking and tail movement.…”

Section: 237-41)mentioning

confidence: 99%

“…4,5,33,52,53) For example, Chen et al showed that w-conotoxin MVIIA, when intrathecally injected at 0.1, 0.5, and 1.0 mg/kg, dose-dependently suppressed formalin-induced nociception in rats. 53) Intrathecal w-conotoxin MVIIA at 1.0 mg/kg, however, caused whole body shaking and tail movement. 53) These data suggest that the safety profile of cilnidipine is better than that of ziconotide.…”

Section: 237-41)mentioning

confidence: 99%

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Suppression of Formalin-Induced Nociception by Cilnidipine, a Voltage-Dependent Calcium Channel Blocker

Koganei

Shoji

Iwata

2009

Biological & Pharmaceutical Bulletin

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Cilnidipine is a 1,4-dihydropyridine-derived voltage-dependent calcium channel (VDCC) blocker and suppresses N-type VDCC currents in addition to L-type VDCC currents. An earlier investigation has suggested that intrathecally injected cilnidipine produces antinociception by blocking N-type VDCCs in mice. The present study using the rat formalin model examined antinociceptive effects of intrathecally and orally administered cilnidipine to elucidate a putative site of antinociception of cilnidipine, assess the efficacy of oral cilnidipine for pain relief, and clarify the mechanism(s) responsible for the antinociceptive effect of oral cilnidipine. Cilnidipine (whether intrathecal or oral) suppressed nociception in phases 1 and 2 of the formalin model. In addition, the potency of oral cilnidipine to suppress formalin-induced nociception in phase 2 was greater than that of oral gabapentin, a clinically available drug for treatment of neuropathic pain. Cilnidipine elicited antinociceptive effects without neurological side-effects including serpentine-like tail movement, whole body shaking, and allodynia. Such side-effects can be induced by higher doses of intrathecal ziconotide, a clinically available N-type VDCC blocker. In contrast, orally administered nifedipine, an L-type VDCC blocker, had no effect on either phase of formalin-induced nociception. These results suggest that cilnidipine acts on the spinal cord to produce antinociception and is efficacious for pain relief after oral administration with better safety profile than that of ziconotide. Furthermore, the failure of orally administered nifedipine to affect formalin-induced nociception raises the possibility that oral cilnidipine produces antinociception through, at least in part, spinal N-type VDCC blockade.

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“…23 GVIA, isolated from the venom of Conus geographus, is a 27-aminoacid peptide that is a potent and selective blocker of N-type calcium channels. MVIIA, isolated from the venom of Conus magnus, is another potent and selective N-type calcium channel blocker.…”

mentioning

confidence: 99%

High-Throughput Screening for N-Type Calcium Channel Blockers Using a Scintillation Proximity Assay

Zhang¹,

Kauffman²,

Yagel³

et al. 2006

SLAS Discovery

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N-type calcium channels located on presynaptic nerve terminals regulate neurotransmitter release, including that from the spinal terminations of primary afferent nociceptors. Accordingly, N-type calcium channel blockers may have clinical utility as analgesic drugs. A selective N-type calcium channel inhibitor, ziconotide (Prialt), is a neuroactive peptide recently marketed as a novel nonopioid treatment for severe chronic pain. To develop a small-molecule N-type calcium channel blocker, the authors developed a 96-well plate high-throughput screening scintillation proximity assay (SPA) for N-type calcium channel blockers using [125 I]-labeled ω-conotoxin GVIA as a channel-specific ligand. Assay reagents were handled using Caliper's Allegro automation system, and bound ligands were detected using a PerkinElmer TopCount. Using this assay, more than 150,000 compounds were screened at 10 µM and approximately 340 compounds were identified as hits, exhibiting at least 40% inhibition of [125 I]GVIA binding. This is the 1st demonstration of the use of [ 125 I]-labeled peptides with SPA beads to provide a binding assay for the evaluation of ligand binding to calcium channels. This assay could be a useful tool for drug discovery. (Journal of Biomolecular Screening 2006:672-677)

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Antinociceptive effects of intrathecally administered huwentoxin-I, a selective N-type calcium channel blocker, in the formalin test in conscious rats

Cited by 33 publications

References 24 publications

Targeting chronic and neuropathic pain: The N-type calcium channel comes of age

Targeting chronic and neuropathic pain: The N-type calcium channel comes of age

Suppression of Formalin-Induced Nociception by Cilnidipine, a Voltage-Dependent Calcium Channel Blocker

High-Throughput Screening for N-Type Calcium Channel Blockers Using a Scintillation Proximity Assay

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