Calcium channel α2δ1 subunit mediates spinal hyperexcitability in pain modulation

Li, Chunying; Zhang, Xiulin; Matthews, Elizabeth; Li, Kang-Wu; Kurwa, Ambereen; Boroujerdi, Amin; Gross, Jimmy; Gold, Michael S.; Dickenson, Anthony H.; Feng, Guoping; Luo, Z. David

doi:10.1016/j.pain.2006.04.022

Cited by 239 publications

(233 citation statements)

References 61 publications

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“…For example, in chronic neuropathic pain states, ␣2-␦ subunits may be upregulated, conferring gabapentin and pregabalin sensitivity. 106,107 Whether there are similar plastic changes in ␣2-␦ subunit expression in epilepsy remains to be determined. Although gabapentin and pregabalin inhibit neurotransmitter release in many systems, there is evidence that this may not require inhibition of calcium influx and may instead be mediated by an interaction of ␣2-␦ (or the calcium-channel complex containing ␣2-␦) with synaptic proteins that are involved in the release or trafficking of synaptic vesicles.…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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“…Experimentally, expression of a 2 d-1, but not a 2 d-2 (another binding site of GBP), is significantly increased in both the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord in animal models of peripheral neuropathic pain. This up-regulation is thought to contribute to the development of allodynia and hyperalgesia [28][29][30][31]. It has thus been proposed that gabapentinoids alleviate neuropathic pain by blocking the trafficking of a 2 d-1 to the presynaptic terminals of DRG neurons and this subsequently leads to reduced Ca 2?…”

Section: Introductionmentioning

confidence: 99%

Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α2δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity

Yang

et al. 2016

Neurosci. Bull.

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The a 2 d-1 subunit of the voltage-gated Ca 2? channel (VGCC) is a molecular target of gabapentin (GBP), which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive effects by disrupting trafficking of the a 2 d-1 subunit to the presynaptic membrane, resulting in decreased neurotransmitter release. We previously showed that GBP has an antiallodynic effect in the first two weeks; but this is followed by insensitivity in the later stage after repeated administration in a rat model of central post-stroke pain (CPSP) hypersensitivity induced by intra-thalamic hemorrhage. To explore the mechanisms underlying GBP insensitivity, the cellular localization and time-course of expression of the a 2 d-1 subunit in both the thalamus and spinal dorsal horn were studied in the same model. We found that the a 2 d-1 subunit was mostly localized in neurons, but not astrocytes and microglia. The level of a 2 d-1 protein increased in the first two weeks after injury but then decreased in the third week, when GBP insensitivity occurred. Furthermore, the a 2 d-1 down-regulation was likely caused by later neuronal loss in the injured thalamus through a mechanism other than apoptosis. In summary, the present results suggest that the GBP receptor a 2 d-1 is mainly expressed in thalamic neurons in which it is up-regulated in the early stage of CPSP but this is followed by dramatic down-regulation, which is likely associated with GBP insensitivity after long-term use.Keywords Central post-stroke pain Á Calcium channel a 2 d subunit Á Gabapentinoid Á Thalamic hemorrhagic stroke Á Thalamus Á Spinal dorsal horn

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“…Ligands for the a2d-subunit (a2d-1 and a2d-2) are thought to exert analgesic effects by reducing Ca 2+ influx into neurons throughout the central nervous system (CNS) via a mechanism not yet fully elucidated (4). It is hypothesized that a reduction in Ca 2+ influx decreases release of excitatory neurotransmitters such as glutamate, norepinephrine, and substance P, which have been implicated in animal models of induced neuropathic pain (4,(7)(8)(9). Recent studies suggest that ligand selectivity for a2d-1 and a2d-2 may result in different clinical outcomes.…”

mentioning

confidence: 99%

Efficacy and Safety of Mirogabalin (DS-5565) for the Treatment of Diabetic Peripheral Neuropathic Pain: A Randomized, Double-Blind, Placebo- and Active Comparator–Controlled, Adaptive Proof-of-Concept Phase 2 Study

Vinik

Rosenstock

Sharma³

et al. 2014

Diabetes Care

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OBJECTIVEWe aimed to identify doses of mirogabalin (DS-5565) providing clinically meaningful efficacy with manageable side effects for treatment of diabetic peripheral neuropathic pain (DPNP). RESEARCH DESIGN AND METHODSAdults ( ‡18 years) with type 1 or 2 diabetes, HbA 1c £10% at screening, and DPNP for ‡6 months were eligible for study participation. Subjects (n = 452) were randomized (2:1:1:1:1:1:1 ratio) to placebo, dose-ranging mirogabalin (5, 10, 15, 20, and 30 mg/day), or pregabalin (300 mg/day) for 5 weeks. The primary end point was weekly change in average daily pain score (ADPS; 0 to 10 numeric rating scale) from baseline to week 5 (minimally meaningful effect, ‡1.0-point decrease versus placebo). ANCOVA was conducted using last observation carried forward, and treatment effect least squares (LS) means were provided for each contrast. Safety assessments included adverse events (AEs), clinical laboratory tests, and electrocardiograms. RESULTSLS mean differences in change in ADPS from baseline to week 5 versus placebo were -0.22, -0.53, -0.94, -0.88, and -1.01 for the mirogabalin 5-, 10-, 15-, 20-, and 30-mg/day treatment groups, respectively, and -0.05 in the pregabalin group (P < 0.05 versus placebo for mirogabalin 15, 20, and 30 mg/day). Most frequent AEs (n = 277) were primarily mild to moderate dizziness (9.4%), somnolence (6.1%), and headache (6.1%); otherwise, mirogabalin was well tolerated. CONCLUSIONSMirogabalin 15, 20, and 30 mg/day had statistically significant reductions in ADPS versus placebo, and mirogabalin 30 mg/day also met the criteria of minimally meaningful effect. Mirogabalin may be a promising new treatment option for patients with DPNP.

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Calcium channel α2δ1 subunit mediates spinal hyperexcitability in pain modulation

Cited by 239 publications

References 61 publications

Molecular Targets for Antiepileptic Drug Development

Molecular Targets for Antiepileptic Drug Development

Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α2δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity

Efficacy and Safety of Mirogabalin (DS-5565) for the Treatment of Diabetic Peripheral Neuropathic Pain: A Randomized, Double-Blind, Placebo- and Active Comparator–Controlled, Adaptive Proof-of-Concept Phase 2 Study

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