Peripheral nerve injury increases contribution of L-type calcium channels to synaptic transmission in spinal lamina II: Role of α2δ–1 subunits. Issue 1 (March 2018)

• Record Type: Journal Article
• Authors: Alles, Sascha RA; Garcia, Esperanza; Balasubramanyan, Sridhar; Jones, Karen; Tyson, John R; Joy, Twinkle; Snutch, Terrance P; Smith, Peter A
• Is Part Of: Molecular pain. Volume 14:Issue 1(2018)
• Publication Date: 2018-03
• Subjects: Allodynia -- pharmacology -- neuropathic pain -- dihydropyridine -- gabapentin -- anti-allodynic -- chronic constriction injury -- central sensitization -- calcium channel blocker -- substantia gelatinosa; Pain -- Molecular aspects -- Periodicals; Pain -- Pathophysiology -- Periodicals; Pain -- Physiological aspects -- Periodicals; 616.0472
• DOI: 10.1177/1744806918765806
• Languages: English
• ISSNs: 1744-8069

Abstract

Background: Following peripheral nerve chronic constriction injury, the accumulation of the α2δ–1 auxiliary subunit of voltage-gated Ca 2+ channels in primary afferent terminals contributes to the onset of neuropathic pain. Overexpression of α2δ–1 in Xenopus oocytes increases the opening properties of Cav 1.2 L-type channels and allows Ca 2+ 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 Ca 2+ 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 Cav 1.2 L-type channels, we tested the effect of the α2δ–1 ligand, gabapentin (100 µM) on currents recorded from HEK293F cells expressing Cav 1.2/β4/α2δ–1 channels and found a significant decrease in peak amplitude with no effect on control Cav 1.2/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.