Role of voltage-dependent calcium channel subtypes in spinal long-term potentiation of C-fiber-evoked field potentials

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.