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

Autor:	Nian Gong, Yanhui Peter Yu, Z. David Luo, Tae Dong Kweon, Benjamin Vo
Rok vydání:	2018
Předmět:	0301 basic medicine Pharmacology education.field_of_study Gabapentin Voltage-dependent calcium channel business.industry Synaptogenesis Spinal cord 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Postsynaptic potential Thrombospondin 4 Neuropathic pain Excitatory postsynaptic potential medicine education business Neuroscience 030217 neurology & neurosurgery medicine.drug
Zdroj:	British Journal of Pharmacology. 175:2348-2361
ISSN:	0007-1188
DOI:	10.1111/bph.14149
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::61734fddce559eb3ad23ad9b12d94124 https://doi.org/10.1111/bph.14149 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.