A wide variety of voltage- and ligand-gated ion channels are needed for the generation and propagation of neuronal action potentials. Many of these channels are generically expressed by a wide variety of neurons. Certain ion channels, however, appear to be localized to neurons conveying nociceptive information. Such channels are potential therapeutic targets; selective blockade could produce analgesia. An understanding of the ion channels expressed on first order Aδ– and C-fibers, as well as second and third order neurons in the dorsal horn and thalamus is obviously of considerable interest to pain research. This chapter is limited to a discussion of voltage-dependent calcium and sodium channels, as well as certain members of the families of potassium and acid-sensing channels, the TRP family, and purinoceptors implicated in pain transmission. Throughout, an emphasis will be placed on studies examining intracranial pain.

Voltage-dependent calcium channels (VDCC) are composed of α₁, α₂δ, β, and γ subunits; the α₁ subunit contains the selective calcium ion pore, a voltage sensor, and the binding site for selective high-threshold VDCC blockers. Ten isoforms of the α₁ subunit have been identified and this forms the basis for the most recent classification system (52). The 10 isoforms are grouped into three families according to their sequence homology (Table 20-1). VDCCs have also been grouped into six classes: L, N, P, Q, R, and T according to their electrophysiologic properties and pharmacologic susceptibility to specific blocking agents. At the most basic level, voltage-gated calcium channels may be divided electrophysiologically into two groups depending on their threshold of activation. Low-threshold VDCCs (T-type VDCCs) are activated at more hyperpolarized membrane voltages relative to the high-threshold (L-, N-, P-, and Q-type) channels (see references in Catterall ([22]).

VDCC are differentially distributed at the neuronal level. P/Q-type VDCCs are located predominantly at presynaptic sites (174,175), N-type are found both pre- and post-synaptically (173), and T- and L-type channels are mainly located on the proximal dendrites and soma of neurons (33,69,172). Synaptic release of neurotransmitters depends on the influx of calcium ions through voltage-gated calcium channels. P/Q-type VDCCs appear to be the most prevalent exocytotic calcium channel within the central nervous system (CNS) (49) controlling the release of excitatory amino acids, monoamines and peptide neurotransmitters (95,127,159,163). Exocytotic release of a variety of neurotransmitters is also inhibited by the N-type blocker ω-conotoxin GVIa (45,95,147,159,163). Excitatory glutaminergic neurotransmission is not completely prevented by blockade of N-type channels, indicating that several VDCCs are involved in neurotransmitter release (159,163). Antagonism of one type of calcium channel may therefore not significantly affect sensory signaling, especially if the presynaptic neuron is strongly depolarized. L-type channels do not appear to have a very significant role in neurotransmitter release in the CNS (although the nature of the stimulus used to evoke neurotransmitter release may be crucially important; nifedipine may inhibit release of substance P from dorsal root ganglion cells when they are depolarized with KCl but not electrical stimulation [73]). L- and N-type channels may have a more important role regulating neuronal membrane properties and synaptic integration. In the dorsal horn of the rat, just as in other neuronal systems such as cortical and hippocampal pyramidal cells, high-threshold calcium currents can generate both regenerative and plateau potentials (77,142,166). Plateau potentials sustained by calcium currents may result in a shift of the resting membrane potential toward threshold levels and contribute to the non-linear response properties observed in dorsal horn neurons (109). The response of a dorsal horn neuron to nociceptive stimulation may therefore be dramatically enhanced
following activation of calcium (possibly L-type VDCCs) mediated plateau potentials (108). Calcium-channel conductance is also subject to the modulatory effects of various neurotransmitters and peptides, which can further affect a neuron’s response characteristics at any given voltage (48,84,112).

It is unsurprising that VDCCs may be targets for compounds with potential analgesic properties. Gabapentin, a drug commonly used for the treatment of neuropathic pain, is also used as a prophylactic treatment for migraine. This calcium-channel modulator inhibits high-threshold VDCCs in dorsal root ganglion neurons (157) and may influence excitatory and inhibitory neurotransmitter release in the spinal dorsal horn (8). The N-type channel blocker ziconotide has also shown promise in clinical trials as a treatment for postoperative and cancer pain (155). Difficulties arise, however, when trying to determine pharmacologically the role of VDCCs in pain pathways. As we shall see, the effects of blocking individual channels may differ depending on the type of drug used in each study, as well as the dosage and their route of administration. The nature of the nociceptive stimulus may also crucially influence the outcome (for comprehensive reviews see Vanegas and Schaible [164] and Prado [129]). It is not clear, for example, whether results from models of chronic inflammatory and neuropathic pain are equally applicable to intracranial nociceptive neurotransmission, although it is reasonable to assume a degree of commonality.

Although it cannot be assumed that the same array of high-threshold VDCCs are involved in spinal and trigeminovascular nociceptive signaling, initial studies do indicate that N- and P/Q-type channels have a role in transmitting sensory information from the dura (50). Blockade of N-type channels effectively inhibits the responses of neurons in the spinal trigeminal nucleus to cold and inflammatory stimulation of the dura mater. Blockade of P/Q-type channels have a less profound effect, whereas L-type block does not have a significant action. Interestingly in both cases application of L- and P/Q-type VDCC blockers produce an increase in spontaneous firing rates, suggesting a disinhibitory action on dorsal horn neurons. Because VDCC blockers were applied to the exposed brainstem and upper cervical cord, the possibility that these effects were the result of actions at other sites, such as in the PAG, cannot be excluded (88). This problem of anatomic localization has been overcome by microiontophoretic ejection of VDCC blockers directly onto trigeminal neurons (149). In this study L-, N- and P/Q-type channels were all shown to contribute to action potential generation by second order neurons in the trigeminocervical complex (Figs. 20-1 and 20-2). Furthermore, neuronal firing triggered by electrical stimulation of the superior sagittal sinus (which is known to cause pain in humans) could also be inhibited by L- and N-type blockers (Fig. 20-3). Although evidence for the effects of L-type channel blockers in the trigeminal nucleus is conflicting, their action on neurogenically induced dural vasodilation suggests that these channels may be involved in trigeminovascular nociceptive pathways in the periphery (1). The potent L-type channel blocker calciseptine can inhibit the presynaptic release of CGRP from trigeminovascular neurons, as did P/Q- and N-type VDCC blockers.

Given the central contribution that VDCCc make toward action potential generation and synaptic neurotransmission, it is hardly surprising that VDCCs have an
important role in pain signaling. Blockade of individual channels may not necessarily prevent transmission of nociceptive information, but certain channels appear to serve a more integral part in pain transmission than others. All VDCCs appear to have complex actions, and in some cases this may involve modulating activity in GABAergic interneurons as well as descending inhibitory circuits. Whether this can be translated into further successful therapeutic interventions remains to be seen.