title: Injury-specific functional alteration of N-type voltage-gated calcium channels in synaptic transmission of primary afferent C-fibers in the rat spinal superficial dorsal horn.
abstract: We investigated functional alterations of voltage-gated calcium channels (VGCCs) in excitatory synaptic transmission from primary afferent A- and C-fibers after peripheral nerve injury. Patch-clamp recordings were performed on substantia gelatinosa (SG) neurons of spinal cord slices with an attached dorsal root, prepared from L5 spinal nerve-ligated (SNL) rats. The effects of neuronal VGCC blockers, ω-conotoxin GVIA (ω-CgTX) for N-type channels and ω-agatoxin IVA (ω-AgaIVA) for P/Q-type channels, on evoked excitatory postsynaptic currents (eEPSCs) by stimulation of A- or C-fibers were studied. Besides, electrophysiological assay using dorsal root ganglion (DRG) and immunohistochemistry were done. In naïve rats, ω-CgTX (0.1-1μM) reduced more effectively A-fiber eEPSCs than C-fiber ones. After nerve injury, ω-CgTX produced great inhibition of C-fiber eEPSCs in slices with the injured L5 dorsal root of SNL model rats, as compared to sham-operated rats. By contrast, in slices with the non-injured L4 one, inhibitory effects of ω-CgTX were not changed. This occurred concurrently with increased expression of N-type VGCCs in L5 spinal dorsal horn and with enhanced Ca(2+) currents through N-type VGCCs in small-sized (C-type) L5 DRG. In terms of A-fiber eEPSCs, ω-CgTX elicited similar inhibition in nerve-injured and sham-operated rats. ω-AgaIVA (0.1μM) had less effect on A- or C-fiber eEPSCs. These results indicate that N-type, but not P/Q-type, VGCCs mainly contribute to excitatory synaptic transmission from A- and C-fibers in the spinal dorsal horn. More importantly, following nerve injury, the functional contribution of N-type VGCCs to nociceptive transmission is increased in the pre-synaptic terminals of injured C-fibers.
authors.affiliation: Pain & Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi Co., Ltd., Toyonaka, Osaka 561-0825, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Takasu
authors.affiliation: Pain & Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi Co., Ltd., Toyonaka, Osaka 561-0825, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Pain & Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi Co., Ltd., Toyonaka, Osaka 561-0825, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Minami
authors.affiliation: Pain & Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi Co., Ltd., Toyonaka, Osaka 561-0825, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Shinohara
authors.affiliation: Pain & Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi Co., Ltd., Toyonaka, Osaka 561-0825, Japan; Business Development, Shionogi Co., Ltd., 1-8, Doshomachi 3-Chome, Chuo-ku, Osaka 541-0045, Japan. Electronic address: akira_kato@shionogi.co.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Kato
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009437:Neuralgia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013376:Substantia Gelatinosa / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type
keywords: EPSCs; N-type voltage-gated calcium channel; Neuropathic pain; Spinal cord; Spinal nerve ligation; Substantia gelatinosa