title: Role of voltage-dependent calcium channel subtypes in spinal long-term potentiation of C-fiber-evoked field potentials.
abstract: Activity-dependent increases in the responsiveness of spinal neurons to their normal afferent input, termed central sensitization, have been suggested to play a key role in abnormal pain sensation. We investigated the role of distinct voltage-dependent calcium channel (VDCC) subtypes in the long-term potentiation (LTP) of C-fiber-evoked field potentials (FPs) recorded in the spinal dorsal horn of rats, that is, a synaptic model to describe central sensitization. When spinally applied, we observed that omega-conotoxin GVIA (ω-CgTx), an N-type VDCC antagonist, produced a dose-dependent and prolonged inhibition of basal C-fiber-evoked FPs in naïve animals. ω-CgTx did not perturb the induction of LTP by high-frequency stimulation (HFS) of the sciatic nerve; however, potentiation was maintained at a lower level. Following the establishment of spinal LTP in naïve animals, the inhibitory effect of ω-CgTx on C-fiber-evoked FPs was significantly increased. Furthermore, in animals with chronic pain produced via peripheral nerve injury, where spinal LTP was barely induced by HFS, basal C-fiber-evoked FPs were strongly inhibited by ω-CgTx. As a result, ω-CgTx exerted a similar inhibitory profile on C-fiber-evoked FPs following the establishment of spinal LTP and chronic pain. In contrast, spinally administered omega-agatoxin IVA (ω-Aga-IVA), a P/Q-type VDCC antagonist, showed little effect on C-fiber-evoked FPs either before or after the establishment of LTP, but strongly suppressed LTP induction. These results demonstrate the requirement of N- and P/Q-type VDCCs in the maintenance and induction of LTP in the spinal dorsal horn, respectively, and their distinct contribution to nociceptive synaptic transmission and its plasticity. In vivo electrophysiological studies demonstrate the distinct and predominant functions of voltage-dependent calcium channel subtypes for spinal long-term potentiation and chronic pain.
authors.affiliation: Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya 467-8603, Japan Pain & Neurology, Discovery Research Laboratories, Shionogi & Co., Ltd., Koka-cho, Koka, Shiga 520-3423, Japan Laboratory of Pharmacology, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ohnami
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Tanabe
authors.forename: Shunji
authors.initials: S
authors.lastname: Shinohara
authors.forename: Keiko
authors.initials: K
authors.lastname: Takasu
authors.forename: Akira
authors.initials: A
authors.lastname: Kato
authors.forename: Hideki
authors.initials: H
authors.lastname: Ono
mesh_terms: D000818:Animals; D001703:Biophysics / Q000379:methods; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology*; D009437:Neuralgia / Q000473:pathology*; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020866:omega-Conotoxin GVIA