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Peripheral nerve injury increases contribution of L-type calcium channels to synaptic transmission in spinal lamina II: Role of α2δ-1 subunits

Alles, SR; Garcia, E; Balasubramanyan, S; Jones, K; Tyson, JR; Joy, T; Snutch, TP; (2018) Peripheral nerve injury increases contribution of L-type calcium channels to synaptic transmission in spinal lamina II: Role of α2δ-1 subunits. Molecular Pain , 14 10.1177/1744806918765806. Green open access

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Abstract

BACKGROUND: Following peripheral nerve chronic constriction injury, the accumulation of the α2δ-1 auxiliary subunit of voltage-gated Ca2+channels in primary afferent terminals contributes to the onset of neuropathic pain. Overexpression of α2δ-1 in Xenopus oocytes increases the opening properties of Cav1.2 L-type channels and allows Ca2+influx at physiological membrane potentials. We therefore posited that L-type channels play a role in neurotransmitter release in the superficial dorsal horn in the chronic constriction injury model of neuropathic pain. RESULTS: Whole-cell recording from lamina II neurons from rats, subject to sciatic chronic constriction injury, showed that the L-type Ca2+channel blocker, nitrendipine (2 µM) reduced the frequency of spontaneous excitatory postsynaptic currents. Nitrendipine had little or no effect on spontaneous excitatory postsynaptic current frequency in neurons from sham-operated animals. To determine whether α2δ-1 is involved in upregulating function of Cav1.2 L-type channels, we tested the effect of the α2δ-1 ligand, gabapentin (100 µM) on currents recorded from HEK293F cells expressing Cav1.2/β4/α2δ-1 channels and found a significant decrease in peak amplitude with no effect on control Cav1.2/β4/α2δ-3 expressing cells. In PC-12 cells, gabapentin also significantly reduced the endogenous dihydropyridine-sensitive calcium current. In lamina II, gabapentin reduced spontaneous excitatory postsynaptic current frequency in neurons from animals subject to chronic constriction injury but not in those from sham-operated animals. Intraperitoneal injection of 5 mg/kg nitrendipine increased paw withdrawal threshold in animals subject to chronic constriction injury. CONCLUSION: We suggest that L-type channels show an increased contribution to synaptic transmission in lamina II dorsal horn following peripheral nerve injury. The effect of gabapentin on Cav1.2 via α2δ-1 may contribute to its anti-allodynic action.

Type: Article
Title: Peripheral nerve injury increases contribution of L-type calcium channels to synaptic transmission in spinal lamina II: Role of α2δ-1 subunits
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1177/1744806918765806
Publisher version: http://dx.doi.org/10.1177/1744806918765806
Language: English
Additional information: Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons AttributionNonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us. sagepub.com/en-us/nam/open-access-at-sage)
Keywords: Allodynia, anti-allodynic, calcium channel blocker, central sensitization, chronic constriction injury, dihydropyridine, gabapentin, neuropathic pain, pharmacology, substantia gelatinosa
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10046233
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