Differential upregulation in DRG neurons of an α2δ-1 splice variant with a lower affinity for gabapentin after peripheral sensory nerve injury

Lana, Beatrice; Schlick, Bettina; Martin, Stuart; Pratt, Wendy S.; Page, Karen M.; Gonçalves, Leônor; Rahman, Wahida; Dickenson, Anthony H.; Bauer, Claudia S.; Dolphin, Annette C.

doi:10.1016/j.pain.2013.12.001

Cited by 40 publications

(45 citation statements)

References 52 publications

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“…In our studies, a marked increase in gabapentin binding affinity was observed for both a 2 d-1 and a 2 d-2 purified in detergent-resistant membrane (lipid raft) fractions compared with total membrane fractions Lana et al, 2014). For example, the binding of 3 H-gabapentin to a 2 d from membranes from mouse cerebellum (predominantly a 2 d-2, which is strongly expressed in Purkinje neurons) gave a K D of approximately 385 nM, whereas the K D was approximately 80 nM in detergent-resistant membranes from the same tissue .…”

supporting

confidence: 49%

“…A change in a 2 d-1 splicing was recently found in rat DRG neurons, after spinal nerve ligation. Increased expression was observed of a minor splice variant (DA + BDC), particularly in small DRG neurons, and this showed a lower affinity for gabapentin (Lana et al, 2014). There are also splice variants of the other a 2 d subunits, but their expression has not been studied in detail (Klugbauer et al, 1999;Barclay and Rees, 2000;Qin et al, 2002).…”

Section: A a 2 D Subunit Genes And Gene Productsmentioning

confidence: 99%

“…It was noted that the cDNA sequence of a 2 d-1 subunit isoforms expressed in rat brain and skeletal muscle showed some divergence (Kim et al, 1992). Three regions, termed A, B, and C, were later identified to be alternatively spliced, with DA + B + C being the major splice variant in brain and in peripheral DRG neurons (Angelotti and Hofmann, 1996;Lana et al, 2014). A change in a 2 d-1 splicing was recently found in rat DRG neurons, after spinal nerve ligation.…”

Section: A a 2 D Subunit Genes And Gene Productsmentioning

confidence: 99%

“…Neuropathic Pain. Peripheral nerve injury has, as one consequence, an increase of a 2 d-1 mRNA in damaged DRG neurons, as evidenced by in situ hybridization (Newton et al, 2001), microarray analysis (Wang et al, 2002), and quantitative polymerase chain reaction (Bauer et al, 2009;Lana et al, 2014). This results in an increase of a 2 d-1 protein in DRGs and their terminals within the spinal cord (Luo et al, 2001;Bauer et al, 2009).…”

Section: A a 2 D Subunit Genes And Gene Productsmentioning

confidence: 99%

See 3 more Smart Citations

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Zamponi¹,

Striessnig²,

Koschak³

et al. 2015

Pharmacol Rev

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903

992

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supporting

confidence: 49%

Section: A a 2 D Subunit Genes And Gene Productsmentioning

confidence: 99%

Section: A a 2 D Subunit Genes And Gene Productsmentioning

confidence: 99%

Section: A a 2 D Subunit Genes And Gene Productsmentioning

confidence: 99%

See 2 more Smart Citations

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Zamponi¹,

Striessnig²,

Koschak³

et al. 2015

Pharmacol Rev

Self Cite

903

992

View full text Add to dashboard Cite

“…Another possibility relates to differences in the properties of ␣2␦-subunits in the different neuron types. This is supported by the recent description of two splice variants of the ␣2␦-1 subunits in DRG neurons (Lana et al 2013). One, designated ␣2␦-1 ⌬AϩBϩC, is found in many brain regions, whereas the other, ␣2␦-1 ⌬AϩB⌬C, is upregulated in small DRG neurons following nerve injury.…”

Section: Discussionmentioning

confidence: 62%

Analysis of the long-term actions of gabapentin and pregabalin in dorsal root ganglia and substantia gelatinosa

Biggs

Boakye

Ganesan

et al. 2014

Journal of Neurophysiology

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of the long-term actions of gabapentin and pregabalin in dorsal root ganglia and substantia gelatinosa. J Neurophysiol 112: 2398 -2412, 2014. First published August 13, 2014; doi:10.1152/jn.00168.2014.-The ␣2␦-ligands pregabalin (PGB) and gabapentin (GBP) are used to treat neuropathic pain. We used whole cell recording to study their long-term effects on substantia gelatinosa and dorsal root ganglion (DRG) neurons. Spinal cord slices were prepared from embryonic day 13 rat embryos and maintained in organotypic culture for Ͼ5 wk (neuronal age equivalent to young adult rats). Exposure of similarly aged DRG neurons (dissociated and cultured from postnatal day 19 rats) to GBP or PGB for 5-6 days attenuated high-voltage-activated calcium channel currents (HVA I Ca ). Strong effects were seen in medium-sized and in small isolectin B 4 -negative (IB 4 Ϫ) DRG neurons, whereas large neurons and small neurons that bound isolectin B 4 (IB 4 ϩ) were hardly affected. GBP (100 M) or PGB (10 M) were less effective than 20 M Mn 2ϩ in suppression of HVA I Ca in small DRG neurons. By contrast, 5-6 days of exposure to these ␣2␦-ligands was more effective than 20 M Mn 2ϩ in reducing spontaneous excitatory postsynaptic currents at synapses in substantia gelatinosa. Spinal actions of gabapentinoids cannot therefore be ascribed to decreased expression of HVA Ca 2ϩ channels in primary afferent nerve terminals. In substantia gelatinosa, 5-6 days of exposure to PGB was more effective in inhibiting excitatory synaptic drive to putative excitatory neurons than to putative inhibitory neurons. Although spontaneous inhibitory postsynaptic currents were also attenuated, the overall long-term effect of ␣2␦-ligands was to decrease network excitability as monitored by confocal Ca 2ϩ imaging. We suggest that selective actions of ␣2␦-ligands on populations of DRG neurons may predict their selective attenuation of excitatory transmission onto excitatory vs. inhibitory neurons in substantia gelatinosa.

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Analgesic effects of co‐administration of mirogabalin and diclofenac sodium on neuropathic pain in rats

Chikubu,

Inage,

Orita

et al. 2024

Journal Orthopaedic Research

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Co‐administration of mirogabalin besylate and nonsteroidal anti‐inflammatory drugs is effective for neuropathic pain; however, mechanism of its action remains unknown. We aimed to evaluate the mechanism of this synergistic effect of the concomitant administration for neuropathic pain using chronic constriction injury model rats. Fifty male Wister rats of 7‐week‐old were used. Right sciatic nerve ligation was performed in 40 rats and they were sub‐divided into four groups: vehicle, mirogabalin, diclofenac sodium and co‐administration of them. Ten rats underwent sham surgery. Fluorogold was attached to sciatic nerve during surgery. Von Frey filament and weight bearing tests were performed on postoperative Day 6 as behavioral assessments and drug was administrated intraperitoneally. Half rats in each group underwent behavioral assessment and perfusion fixation using 4% paraformaldehyde on postoperative Day 7 and remaining on postoperative Day 14. Subsequently, dorsal root ganglion at L4 to L6 was collected and examined immunohistochemistry for calcitonin gene‐related peptide, and their immunoreactivity in fluorogold‐labeled neurons was measured. Spinal cord at lumbar swelling was resected, immunostained for ionized‐calcium‐binding adapter molecule‐1 and glial fibrillary acidic protein, and immunoreactive neurons in dorsal horn of spinal cords were calculated as the occupancy of them. Mirogabalin suppresses the neuropeptide‐release from presynaptic afferent neuron directly and it resulted in suppressing glia cells activation. Diclofenac sodium inhibits cyclooxygenase‐2 and prostaglandin production, related to allodynia. These effects of mirogabalin and diclofenac sodium, respectively, inhibited glia cells strongly, which is presumed to be one of the mechanisms for the effectiveness of their co‐administration for neuropathic pain.

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Differential upregulation in DRG neurons of an α2δ-1 splice variant with a lower affinity for gabapentin after peripheral sensory nerve injury

Abstract: SummaryA minor α2δ-1 splice-variant, (ΔA+BΔC), with reduced affinity for gabapentin, is differentially upregulated in DRG neurons following ligation. This could influence the efficacy of gabapentin.

Cited by 40 publications

References 52 publications

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Analysis of the long-term actions of gabapentin and pregabalin in dorsal root ganglia and substantia gelatinosa

Analgesic effects of co‐administration of mirogabalin and diclofenac sodium on neuropathic pain in rats

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