ABSTRACT
We investigated the contribution of L-, N- and P/Q-type Ca(2+) channels to the [Ca(2+)](i) changes, evoked by kainate, in the cell bodies of hippocampal neurons, using a pharmacological approach and Ca(2+) imaging. Selective Ca(2+) channel blockers, namely nitrendipine, omega-Conotoxin GVIA (omega-GVIA) and omega-Agatoxin IVA (omega-AgaIVA) were used. The [Ca(2+)](i) changes evoked by kainate presented a high variability, and were abolished by NBQX, a AMPA/kainate receptor antagonist, but the N-methyl-D-aspartate (NMDA) receptor antagonist, D-AP5, was without effect. Each Ca(2+) channel blocker caused differential inhibitory effects on [Ca(2+)](i) responses evoked by kainate. We grouped the neurons for each blocker in three subpopulations: (1) neurons with responses below 60% of the control; (2) neurons with responses between 60% and 90% of the control, and (3) neurons with responses above 90% of the control. The inhibition caused by nitrendipine was higher than the inhibition caused by omega-GVIA or omega-AgaIVA. Thus, in the presence of nitrendipine, the percentage of cells with responses below 60% of the control was 41%, whereas in the case of omega-GVIA or omega-AgaIVA the values were 9 or 17%, respectively. The results indicate that hippocampal neurons differ in what concerns their L-, N- and P/Q-type Ca(2+) channels activated by stimulation of the AMPA/kainate receptors.
Subject(s)
Calcium Channels, L-Type/metabolism , Calcium Channels, N-Type/metabolism , Calcium Channels, P-Type/metabolism , Calcium Channels, Q-Type/metabolism , Excitatory Amino Acid Agonists/pharmacology , Hippocampus , Kainic Acid/pharmacology , Neurons/drug effects , Animals , Calcium/metabolism , Calcium Channel Blockers/metabolism , Cells, Cultured , Excitatory Amino Acid Antagonists/metabolism , Hippocampus/cytology , Hippocampus/drug effects , Hippocampus/metabolism , Neurons/cytology , Neurons/metabolism , Nitrendipine/metabolism , Quinoxalines/metabolism , Rats , Rats, Wistar , omega-Agatoxin IVA/metabolism , omega-Conotoxin GVIA/metabolismABSTRACT
We have recently shown that injection of the P/Q-type (Ca(v)2.1/alpha(1A)) calcium channel blocker, omega-agatoxin IVA, into the periaqueductal gray (PAG) facilitates meningeal dural stimulation-evoked trigeminal nociceptive processing. We injected the GABA(A) antagonist bicuculline into the PAG in addition to the agatoxin and observed bicuculline's effect on neurons responding to dural stimulation recorded in the trigeminal nucleus caudalis of rats in order to determine if P/Q channel-mediated changes acted through GABAergic mechanisms. The inhibition of trigeminal nociceptive neurons characteristic of bicuculline administered into the PAG was maintained in the presence of blocked PAG P/Q-type calcium channels. This suggests the PAG descending pain modulatory pathway is not affected by P/Q-type calcium channel blockade at the postsynaptic GABAergic inhibitory interneuron and the facilitation produced by agatoxin is mediated by another mechanism. These findings have implications for disorders involving the PAG or P/Q-type channels, such as migraine, in particular for the development of preventative treatments, suggesting GABAergic and voltage-gated calcium channels could be separately modulated.