Injury-induced maladaptation and dysregulation of calcium channel α δ subunit proteins and its contribution to neuropathic pain development.

Unlabelled: Voltage-gated calcium channels (VGCCs) play important roles in physiological functions including the modulation of neurotransmitter release, neuronal network activities, intracellular signalling pathways and gene expression. Some pathological conditions, including nerve injuries, can cause the dysregulation of VGCCs and their subunits. This in turn can lead to a functional maladaptation of VGCCs and their subunits, which can contribute to the development of disorders such as pain sensations. This review has summarized recent findings related to maladaptive changes in the dysregulated VGCC α δ subunit (Ca α δ ) with a focus on exploring the mechanisms underlying the contribution of Ca α δ to pain signal transduction. At least under neuropathic pain conditions, the dysregulated Ca α δ can modulate VGCC functions as well as other plasticity changes. The latter includes abnormal excitatory synaptogenesis resulting from its interactions with injury-induced extracellular matrix glycoprotein molecule thrombospondins, which is independent of the VGCC functions. Blocking Ca α δ with gabapentinoids can reverse neuropathic pain significantly with relatively mild side effects, but only in a small population of neuropathic pain patients due to reasons yet to be explored. There are emerging data suggesting that early preventive treatment with gabapentinoids can prevent aberrant excitatory synapse formation and the development of chronic pain. If these findings are confirmed clinically, this could be an attractive approach for neuropathic pain management.

Linked Articles: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.