Department of Pharmacology, University of California, Irvine School of Medicine, Irvine, CA, USA.
Department of Anesthesiology & Perioperative Care, University of California, Irvine School of Medicine, Irvine, CA, USA.
Br J Pharmacol. 2018 Jun;175(12):2348-2361. doi: 10.1111/bph.14149. Epub 2018 Mar 1.
Nerve injury induces concurrent up-regulation of the voltage-gated calcium channel subunit Ca α δ 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 Ca α δ 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.
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.
Only presynaptic, but not postsynaptic, Ca α δ subunits interacted with TSP4 to initiate excitatory synaptogenesis through a pathway modulated by T-type calcium channels. Ca α δ /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.
Ca α δ /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 Ca α δ /TSP4-initiated abnormal synapse formation.
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.
神经损伤会导致背根神经节和背侧脊髓中的电压门控钙通道亚基 Caαδ 和细胞外基质蛋白血小板反应蛋白 4（TSP4）同时上调，导致神经性疼痛状态的发生。这些蛋白质的相互作用促进了异常的兴奋性突触形成，通过未知的机制导致神经性疼痛状态的发展。我们研究了 Caαδ 亚基和 TSP4 对突触形成的贡献，以及体外涉及的途径，以及加巴喷丁是否可以阻断这种过程和体内疼痛的发展。
使用感觉神经元和脊髓神经元的共培养系统来研究每种蛋白质对突触形成的贡献以及涉及的途径。在 TSP4 注射小鼠中研究了加巴喷丁的抗突触形成作用。
只有突触前 Caαδ 亚基，而不是突触后 Caαδ 亚基，与 TSP4 相互作用，通过 T 型钙通道调节的途径引发兴奋性突触形成。Caαδ/TSP4 相互作用对于已经形成的突触的维持不是必需的。体内，早期而非延迟，低剂量加巴喷丁治疗阻断了这种途径和疼痛状态的发展。
Caαδ/TSP4 相互作用对于感觉神经元和脊髓神经元之间异常突触形成的起始是关键的，但不是维持所必需的。该过程被早期而非延迟的加巴喷丁治疗所阻断。早期干预加巴喷丁可能会预防由 Caαδ/TSP4 引发的异常突触形成导致的损伤诱导的慢性疼痛的发展。
本文是关于靶向离子通道治疗慢性疼痛的最新进展专题的一部分。要查看本部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.
