Gabapentin prevents synaptogenesis between sensory and spinal cord neurons induced by thrombospondin-4 acting on pre-synaptic Cav α2 δ1 subunits and involving T-type Ca2+ channels.

BACKGROUND AND PURPOSE: Nerve injury induces concurrent up-regulation of the voltage-gated calcium channel subunit Cav α2 δ1 and the extracellular matrix protein thrombospondin-4 (TSP4) in dorsal root ganglia and dorsal spinal cord, leading to the development of a neuropathic pain state. Interactions of these proteins promote aberrant excitatory synaptogenesis that contributes to neuropathic pain state development through unknown mechanisms. We investigated the contributions of Cav α2 δ1 subunits and TSP4 to synaptogenesis, and the pathways involved in vitro, and whether treatment with gabapentin could block this process and pain development in vivo. EXPERIMENTAL APPROACH: A co-culture system of sensory and spinal cord neurons was used to study the contribution from each protein to synaptogenesis and the pathway(s) involved. Anti-synaptogenic actions of gabapentin were studied in TSP4-injected mice. KEY RESULTS: Only presynaptic, but not postsynaptic, Cav α2 δ1 subunits interacted with TSP4 to initiate excitatory synaptogenesis through a pathway modulated by T-type calcium channels. Cav α2 δ1 /TSP4 interactions were not required for maintenance of already formed synapses. In vivo, early, but not delayed, treatment with low-dose gabapentin blocked this pathway and the development of the pain state. CONCLUSIONS AND IMPLICATIONS: Cav α2 δ1 /TSP4 interactions were critical for the initiation, but not for the maintenance, of abnormal synapse formation between sensory and spinal cord neurons. This process was blocked by early, but was not reversed by delayed, treatment with gabapentin. Early intervention with gabapentin may prevent the development of injury-induced chronic pain, resulting from Cav α2 δ1 /TSP4-initiated abnormal synapse formation. 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.