The α2δ auxiliary subunits of voltage-gated calcium channels enhance calcium currents and affect their properties, but their mechanism of action is not well understood. We have recently shown that α2δ subunits are glycosyl phophatidyl inositol (GPI)-achored proteins (Davies et al., 2010), and this is essential for their function, and explains their localization in lipid raft fractions (Davies et al., 2006). The anti-epileptic and anti-nociceptive drugs gabapentin (GBP) and pregabalin (PGB) are known to bind to α2δ-1 and α2δ-2, and the α2δ-1 target is essential for the antihyperalgesic action of this drug (Field et al., 2006). We have found that acute application of GBP does not affect calcium currents in several different systems. However, chronic application of GBP to cultured cells reduces both calcium currents and cell-surface expression of heterologously expressed α2δ and α1 subunits (Hendrich et al., 2008), and PGB also affects α2δ trafficking in vivo (Bauer et al., 2009). This process involves an inhibition of trafficking through the recycling endosomes (Tran-Van-Minh & Dolphin, 2010). Our evidence indicates that gabapentinoid drugs act chronically to impair the trafficking function of α2δ subunits and the associated α1 calcium channel subunits. Evidence from numerous studies has identified an important role for α2δ-1 in neuropathic pain. The mRNA and protein for α2δ-1 are up-regulated in dorsal root ganglion (DRG) neurons following spinal nerve ligation (SNL), a model of neuropathic pain, an increase which correlates with the onset of mechanical hypersensitivity (Bauer et al., 2009). In a recent study, we have examined the role of α2δ-1 in sensory neuron function by examining sensory processing and the development of experimental neuropathic pain in α2δ-1 knockout mice (Fuller-Bicer et al., 2009). We have found that α2δ-1 gene deletion results in reduced baseline sensitivity to cold and mechanical stimuli, and a marked delay in the onset of mechanical hypersensitivity following nerve injury. This is coupled with a reduction in the proportion of DRG neurons sensitive to menthol in α2δ-1 knockout mice, suggesting defects in specific sensory modalities and that α2δ-1 is essential for the rapid development of behavioural hypersensitivity following nerve damage