The present experiments demonstrated modulating actions by zolmitriptan on IBa of the rat isolated TGNs. Zolmitriptan inhibited HVA Ca2+ currents carried by Ba2+ in a concentration-dependent manner within the concentration range between 0.1 μM and 100 μM by acting on 5HT1B/1D receptor through Gi/o protein-coupled pathway.
5HT receptors are divided into 7 families, 5HT1~7 receptors, on the basis of their amino acid sequences and other properties. 5HT1 receptors are further subdivided according to their physiological functions, binding affinity and other features . The present study showed that GR127935, a potent 5HT1B/1D receptor antagonist abolished the effect of zolmitriptan, meaning that zolmitriptan acted on 5HT1B/1D receptor.
5HT1B and/or 1D subtypes are known as G-protein mediated receptors. In the present study, pretreatment with PTX inhibited the IBa inhibition by zolmitriptan, indicating the involvement of Gi/o protein coupled pathway. This observation might be compatible with the previous reports that an increase in intracellular Ca2+ level by 5HT1 receptor is associated with activation of Gi/Go protein coupled pathway [13, 14] and that the modulation of neuronal voltage-gated Ca2+ channel is mediated by receptors coupled to PTX-sensitive G proteins [15, 16]. In this context, possible involvement of stimulatory of G-proteins (Gs) in the zolmitriptan action should be further investigated by using cholera toxin. A recent report shows that sumatriptan could activate the other second messenger MAPK pathway leading to changes in intracellular Ca2+ changes . This possibility for the action of zolmitriptan remains to be considered in future.
It is reported that triptans, antimigraine drugs might inhibit the release of vasoactive neuropeptide from trigeminovascular nerve endings and also inhibit transmission of nociceptive impulses to second-order neurons of the trigeminocervical complex, resulting in the antimigraine effect of triptan . It is known that the trigeminal ganglion possesses small to medium size 5HT1B/1D receptor positive peptidergic neurons [4, 5] and furthermore that antimigraine drugs could block synaptic transmission between meningeal nociceptors and central trigeminal neurons presynaptically . All of these suggest that HVA Ca2+ channels, highly responsible to neurotransmitter release from presynaptic terminal, might be involved in the antimigraine effects of triptans. Indeed the present study showed that HVA IBa of TGNs was affected by zolmitriptan, a 5HT1B/1D agonist, strongly advocating the idea that triptans inhibited neurotransmitter release from peripheral or central presynaptic terminal through HVA Ca2+ channels.
It is important to determine which subtypes of HVA Ca2+ channels might essentially contribute to the release of different neurotransmitters from various classes of neurons. Some paper mentioned simply about HVA Ca2+ subtype on trigeminal neurons, but there is no consensus about which subtypes mainly contribute yet. Ebersberger et al shows that discharge patterns of trigeminal second order neurons with dural input are different in the presence of each HVA Ca2+ subtype blockade , On the other hand, Hong et al showed that N- and P/Q-channels are important for the release of CGRP from perivascular TGNs  and the release of CGRP is shown to be prevented when N-, P/Q- or L- channels are blocked on trigeminal vascular neuron . The present study demonstrated that the inhibition of zolmitriptan-sensitive IBa in small-medium TGNs depended mainly on activation of P/Q- and R-type channels.
P/Q-type Ca2+ channels are reported to locate in all brain structure  and also in the trigeminal ganglia . Furthermore, α-eudesmol, a P/Q-type channel blocker, inhibits the release of a neuropeptide from perivascular trigeminal sensory nerves . These observations may support our present findings that P/Q-type channels might be possible sites on which zolmitriptan could act in cultured neonatal rat TGNs. Although N-type is also known to locate in DRG neurons [22–24], a few studies show the N-type channel dominance in TGNs. The present study with ω-CgTx also could not statistically demonstrate an appreciable involvement of N-type channels in the inhibition of zolmitriptan-sensitive IBa of cultured rat TGNs.
R-type Ca2+ channels are shown to locate presynaptically in the central nervous system, but the transmitter release mediated by R-type channels is less efficient than that by P/Q-and N-type channels . In the process of development, R-type channels are replaced by P/Q-type ones in the central synaptic transmission . There are similar results for Ca2+ channel subtypes obtained from neonatal and adult TGNs; in neonatal 4% are provided with P/Q-type while 15% with R-type one ; in adult 40% with P/Q-type while 5% to R-type . In this context, the present study, for the first time, demonstrated possible involvement of R- as well as P/Q-type channels in the actions of zolmitriptan on the cultured neonatal rat TGNs.
Although zolmitriptan (0.1~100 μM) inhibited IBa of cultured TGNs, it is difficult to determine the effective concentration of zolmitriptan acting in vivo on the trigeminal ganglion. Sumatriptan is reported to induce discharges in dural primary afferent neurons at concentrations between 0.24 and 24 μM  and also cause vasocontraction in rat isolated vena portae smooth muscle at concentrations between 0.001 and 10 μM ; these indicate that actions of two triptans could be exerted at similar concentrations.