Mechanisms of the gabapentinoids and α 2 δ-1 calcium channel subunit in neuropathic pain

Abstract

The gabapentinoid drugs gabapentin and pregabalin are key front-line therapies for various neuropathies of peripheral and central origin. Originally designed as analogs of GABA, the gabapentinoids bind to the α 2 δ-1 and α 2 δ-2 auxiliary subunits of calcium channels, though only the former has been implicated in the development of neuropathy in animal models. Transgenic approaches also identify α 2 δ-1 as key in mediating the analgesic effects of gabapentinoids, however the precise molecular mechanisms remain unclear. Here we review the current understanding of the pathophysiological role of the α 2 δ-1 subunit, the mechanisms of analgesic action of gabapentinoid drugs and implications for efficacy in the clinic. Despite widespread use, the number needed to treat for gabapentin and pregabalin averages from 3 to 8 across neuropathies. The failure to treat large numbers of patients adequately necessitates a novel approach to treatment selection. Stratifying patients by sensory profiles may imply common underlying mechanisms, and a greater understanding of these mechanisms could lead to more direct targeting of gabapentinoids.

Keywords: Alpha 2 delta 1; calcium channel subunit; gabapentin; neuropathic pain; pregabalin.

Figure 1

Structure of GABA, gabapentin and pregabalin.

Figure 2

Topology of α ₂ δ subunits. All subunits are products of a single‐gene cleaved posttranslation and joined by disulphide bridges (De Jongh et al. 1990). The δ subunit is anchored to the plasma membrane through a glycosylphosphatidylinositol anchor (Davies et al. 2010). Putative N‐glycosylation sites have been identified on both domains. The approximate position of the von Willebrand factor A domain (required for trafficking of α ₁ subunit of VGCCs (Canti et al. 2005)) is shown in close proximity to gabapentin and pregabalin‐binding site in α ₂ δ‐1 and α ₂ δ‐2 (RRR).

Figure 3

Sites of action of gabapentinoid drugs. Nerve injury induces synaptic plasticity, central sensitization, increased descending serotonergic facilitation and reduced descending noradrenergic inhibition of spinal neuronal excitability. Gabapentinoid drugs have been demonstrated to inhibit trafficking of the α ₂ δ‐1 subunit from DRG neurones to central terminals in the dorsal horn. Spinally administered gabapentinoids in neuropathic rats reduce dorsal horn neuronal responses to peripheral stimuli. This effect is highly influenced by an increase in descending serotonergic facilitations. Gabapentinoids have also been proposed to restore deficiencies of descending noradrenergic inhibition, although the spinal effects do not depend on this pathway. Gabapentinoids reduce elevated spontaneous and evoked activity in the amygdala, though this may occur secondary to reduced spinal neuronal activity. (GBPs, gabapentinoids; DRG, dorsal root ganglia; NA, noradrenaline; PAG, periaqueductal gray; Ce, central nucleus of the amygdala; H, hypothalamus; LC, locus coeruleus; IC, insula cortex; ACC, anterior cingulate cortex; RVM, rostral ventromedial medulla).

Figure 4

Cellular mechanisms of gabapentinoid drugs in the dorsal horn. α ₂ δ‐1 and β subunits of VGCCs mediate forward trafficking of channels from the endoplasmic reticulum, and this process can be facilitated by PKC. Descending facilitations activating presynaptic ionotropic 5‐HT ₃Rs results in membrane depolarization and may have consequences for VGCC activity. Gabapentinoids inhibit rab11‐dependent recycling of endosomal VGCCs while having no effect on the interaction between α ₂ δ‐1 and VGCCs at the membrane. An inhibition of channel recycling results in reduced channel expression at the synaptic membrane and a decrease in transmitter release. Independent of its association with VGCCs, α ₂ δ‐1 can interact with extracellular matrix proteins such as thrombospondins and mediate excitatory synaptogenesis, a process that is also inhibited by gabapentin. (GBPs, gabapentinoids; PKC, protein kinase C; VGCCs, voltage‐gated calcium channels).