Autoradiographic localization of calcium channels with [125I]ω-conotoxin in rat brain

Kerr, Lynne M.; Filloux, Francis; Olivera, Baldomero M.; Jackson, Heidi H.; Wamsley, James K.

doi:10.1016/0014-2999(88)90501-8

Cited by 123 publications

(44 citation statements)

References 5 publications

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“…3 These results are largely in agreement with autoradiographic analyses using radiolabeled -conotoxin-GVIA, although they suggest a more specific distribution compared with that reported for a monoclonal antibody against -conotoxin-GVIA itself. 14 In agreement with pharmacological analyses showing that blockade of Ntype channels disrupts a portion of central neurotransmission, 4 ␣ 1B -subunits are found highly concentrated at a limited subset of presynaptic terminals in the central and peripheral nervous systems. 3 N-type channel activity can be modulated by activation of a number of G protein-coupled receptors (GPCRs).…”

Section: N-type Calcium Channelssupporting

confidence: 73%

“…14,28 These primary afferents (mainly C-fibers and A-␦ fibers) are implicated in the sensation of a variety of noxious painful stimuli including thermal, mechanical, and inflammatory. Critically, block of N-type currents inhibits the release of neuropeptides substance P and calcitonin gene-related peptide (CGRP) from sensory neurons.…”

Section: N-type Calcium Channels As a Primary Therapeutic Target For mentioning

confidence: 99%

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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: N-type Calcium Channelssupporting

confidence: 73%

Section: N-type Calcium Channels As a Primary Therapeutic Target For mentioning

confidence: 99%

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

2005

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“…Intrathecal delivery of N-type ( -conopeptides), but not L-or P-type, VGCC antagonists suppresses allodynia in neuropathic rat models (Chaplan et al, 1994b;Calcutt and Chaplan, 1997). Autoradiographic studies showed the highest density of conopeptide-binding sites in the spinal dorsal horn (lamina I and II) where primary afferents terminate (Kerr et al, 1988;Takemura et al, 1989). N-VGCCs are also found in dorsal root ganglion (DRG) neurons where they are differentially modulated after sciatic nerve damage (Abdulla and Smith, 1997).…”

Section: Abstract: ␣ 2 ␦ Calcium Channel Subunit; Peripheral Nerve Imentioning

confidence: 99%

Upregulation of Dorsal Root Ganglion α₂δ Calcium Channel Subunit and Its Correlation with Allodynia in Spinal Nerve-Injured Rats

et al. 2001

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Peripheral nerve injury can lead to a persistent neuropathic pain state in which innocuous tactile stimulation elicits pain behavior (tactile allodynia). Spinal administration of the anticonvulsant gabapentin suppresses allodynia by an unknown mechanism. In vitro studies indicate that gabapentin binds to the ␣ 2 ␦-1 (hereafter referred to as ␣ 2 ␦) subunit of voltage-gated calcium channels. We hypothesized that nerve injury may result in altered ␣ 2 ␦ subunit expression in spinal cord and dorsal root ganglia (DRGs) and that this change may play a role in neuropathic pain processing. Using a rat neuropathic pain model in which gabapentin-sensitive tactile allodynia develops after tight ligation of the left fifth and sixth lumbar spinal nerves, we found a Ͼ17-fold, time-dependent increase in ␣ 2 ␦ subunit expression in DRGs ipsilateral to the nerve injury. Marked ␣ 2 ␦ subunit upregulation was also evident in rats with unilateral sciatic nerve crush, but not dorsal rhizotomy, indicating a peripheral origin of the expression regulation. The increased ␣ 2 ␦ subunit expression preceded the allodynia onset and diminished in rats recovering from tactile allodynia. RNase protection experiments indicated that the DRG ␣ 2 ␦ regulation was at the mRNA level. In contrast, calcium channel ␣ 1B and ␤ 3 subunit expression was not co-upregulated with the ␣ 2 ␦ subunit after nerve injury. These data suggest that DRG ␣ 2 ␦ regulation may play an unique role in neuroplasticity after peripheral nerve injury that may contribute to allodynia development. Key words: ␣ 2 ␦ calcium channel subunit; peripheral nerve injury; rhizotomy; allodynia; dorsal root ganglia; spinal cord; sensory neuronsPeripheral nerve injury may lead to neuropathic syndromes characterized by both spontaneous and evoked painful sensations. Allodynia, or an exaggerated response to otherwise innocuous tactile stimuli, is considered both a hallmark and the most troublesome of these syndromes (Price et al., 1989;Wahren and Torebjork, 1992;Koltzenburg et al., 1994). The molecular mechanisms of neuropathic pain states are not clear. It has been hypothesized that disordered sensory processing arises from long-term changes in the function of sensory afferents and the organization of sensory input into the dorsal horn (Coderre et al., 1993;Woolf and Doubell, 1994).Pharmacological evidence suggests that spinal N-type voltagegated calcium channels (N-VGCCs) play a role in neuropathic pain transduction. Intrathecal delivery of N-type ( -conopeptides), but not L-or P-type, VGCC antagonists suppresses allodynia in neuropathic rat models (Chaplan et al., 1994b;Calcutt and Chaplan, 1997). Autoradiographic studies showed the highest density of conopeptide-binding sites in the spinal dorsal horn (lamina I and II) where primary afferents terminate (Kerr et al., 1988;Takemura et al., 1989). N-VGCCs are also found in dorsal root ganglion (DRG) neurons where they are differentially modulated after sciatic nerve damage (Abdulla and Smith, 1997).High-threshold neuronal VGCCs contain thr...

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“…[1], and [*251]w-ctx GVI A binds specifically to regions of rat brain [25]. We found that preincubation of low6 M [r2'I]w-ctx GVIA with anti-w-&r GVIA monoclonal antibody for 30 min at 4'C blocked toxin binding to rat brain synaptosomes (data not shown).…”

Section: Detection Of Toxin In Biological Samplesmentioning

confidence: 81%

Monoclonal antibodies against the presynaptic calcium channel antagonist ω‐conotoxin GVI A from cone snail poison

et al. 1990

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Monoclonaf antibodies have been prepared against oxonotoxin GVI A, a peptide isolated from marine snails of the genus Conus ~Con~ge~ru~h~ a+ and Conus magus). This toxin is a blocker of select presynaptic Ca channels in the central nervous system. Antigenic o-conotoxin GVI A was synthesized as a covalent conjugate with bovine serum albumin and injected S.C. An ELISA assay combined with a competitive inhibition assay was used to select and characterize monoclonal antibodies able to recognize and bind the free toxin. Several of the antibodies were found to block w-conotoxin GVI A inhibition of %a transport into rat brain synaptosomes and to block w-conotoxin GVI A binding to membranes from the same preparation, The antibodies recognize native, synthetic toxin, and are useful for analysis of toxin in biological fluids.

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Autoradiographic localization of calcium channels with [125I]ω-conotoxin in rat brain

Cited by 123 publications

References 5 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

Upregulation of Dorsal Root Ganglion α₂δ Calcium Channel Subunit and Its Correlation with Allodynia in Spinal Nerve-Injured Rats

Monoclonal antibodies against the presynaptic calcium channel antagonist ω‐conotoxin GVI A from cone snail poison

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Autoradiographic localization of calcium channels with [125I]ω-conotoxin in rat brain

Cited by 123 publications

References 5 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

Upregulation of Dorsal Root Ganglion α2δ Calcium Channel Subunit and Its Correlation with Allodynia in Spinal Nerve-Injured Rats

Monoclonal antibodies against the presynaptic calcium channel antagonist ω‐conotoxin GVI A from cone snail poison

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Upregulation of Dorsal Root Ganglion α₂δ Calcium Channel Subunit and Its Correlation with Allodynia in Spinal Nerve-Injured Rats