Insights Into the Pharmacological Targeting of the Trigeminocervical Complex in the Context of Treatments of Migraine

Simon Akerman; Marcela Romero-Reyes

Disclosures

Expert Rev Neurother. 2013;13(9):1041-1059. 

In This Article

Established Therapeutics

Serotonin 5-HT1B/1D Receptors

Ergot alkaloids such as ergotamine and dihydroergotamine were the first relatively specific anti-migraine drugs used in the abortive treatment of migraine. However, their response as a treatment can be unpredictable, particularly with nasal forms, and they have a complex pharmacology that includes, but is not limited to, 5-HT1B/1D receptor agonism.[39] Intravenous injection is far more reliable but less attractive to patients, and the more recent development of inhaled forms of dihydroergotamine have proved more predictable and tolerated by patients.[40] However, the triptan class of drugs, specific 5-HT1B/1D receptor agonists, were the first class of molecules designed specifically for the acute treatment of migraine.[41,42] They were originally developed on the basis of a peripheral hypothesis of migraine, where vasodilation of cranial blood vessels, and neurogenic dural plasma extravasation, a sterile dural inflammatory response, are the primary events in activating the trigeminovascular system.[43,44] The presence of 5-HT1B receptors on human intracranial arteries[45] and evidence that 5-HT1B receptor activation specifically causes arterial vasoconstriction[46] supported the view that sumatriptan may be acting, in part, to constrict dilated blood vessels during migraine. Evidence that sumatriptan inhibits neurogenic dural inflammation in animals also supported this hypothesis.[47] One of the primary side effects of triptan molecules is their potential cardiovascular contraindications, due to the presence of 5-HT1B receptors on coronary arteries.[48–50] Subsequently, confirmationally restricted analogs of triptan molecules, termed extravasation inhibitors, were developed that are without cardiovascular side effects at doses that do not activate 5-HT1B/1D receptors.[51] These molecules were screened in preclinical assays of neurogenic dural inflammation,[52,53] but they failed when they reached clinical trial.[54,55] These data would seem to indicate that the therapeutic mechanism of action of triptans was not by inhibiting plasma protein extravasation but by a different mechanism of action, and that this therapeutic mechanism is not relevant to migraine.

The presence of 5-HT1D receptors on peripheral trigeminal nerve fibers[45,56] and 5-HT1B/1D receptors on trigeminal ganglion cells[57–59] in humans and rats, and 5-HT1B/1D receptors on central trigeminal neurons in humans,[45,60,61] indicates that a neural mechanism of action is also possible. The view that migraine is a disorder of the brain, where central sensitization of trigeminovascular neurons and activation of brain stem nuclei that either exacerbates or contributes independently to activation of trigeminovascular neurons, also points to a neural locus of action, which the data support. There is specific binding of [3H]-sumatriptan in the TCC in human,[62] cat[63] and guinea pig,[64] and [3H]-zolmitriptan in the cat,[65] which demonstrates a locus of action of 5-HT1B/1D receptor agonists. Furthermore, neuronal cells of the TCC, that are activated by dural nociceptive electrical stimulation in animal models, are inhibited by eletriptan,[66] naratriptan,[67,68] zolmitriptan[69] and rizatriptan.[70] The specificity of responses at the TCC to 5-HT1B/1D receptors is demonstrated by reversal of the effects of naratriptan by the specific 5-HT1B/1D receptor antagonist, GR127935.[67] The failure of specific 5-HT1A receptor agonists in the same assay would suggest they have no role.[71] Sumatriptan does not inhibit trigeminal neurons when activated by dural electrical stimulation unless the blood–brain barrier is disrupted.[72] However, sumatriptan is able to prevent central sensitization of TCC neurons, but not abort central sensitization, possibly via an action on the nerve endings at the TCC or meningeal nociceptors.[73,74] These data indicate that triptans are acting on neural sites in the trigeminovascular system to inhibit neuronal activation.

It is still not clear whether 5-HT1B,1D or both receptors are crucial in the treatment of migraine. Subsequent to the triptans there was the development of specific 5-HT1D receptor agonists that lack the vascular issues of the triptans, without the 5-HT1B component, but still targeting the neuronal sites in the trigeminovascular system. A 5-HT1D receptor agonist, PNU-109291, is a potent inhibitor of neurogenic dural inflammation and capsaicin-induced Fos expression in the TCC[75] with no vascular effects. However, another 5-HT1D receptor agonist, PNU-142633, which went into clinical trial was ineffective in the acute treatment of migraine.[76] Although it has been argued that it has relatively weak efficacy at the 5-HT1D receptor and may perhaps have been the wrong molecule for this target. Since 5-HT1D receptors are found at trigeminal nerve terminals and their action will shut down neuronal firing, if a molecule was developed as efficacious as sumatriptan at the 5-HT1D receptor, without the vascular effects of 5-HT1B receptor efficacy, it may still prove a useful neuronal target, within the TCC, for the treatment of migraine.

The above physiological studies have all used systemic, intravenous, administration of compounds, which intimate the TCC as the locus of therapeutic action. However, none of these data definitively confirm this. Direct microiontophoresis of 5-HT1B/1D receptor agonists, sumatriptan and zolmitriptan, on dural-evoked neurons of the TCC results in reversible inhibition of these neurons.[77,78] Furthermore, in preclinical studies triptans have also been demonstrated to modulate basal and dural-evoked nociceptive activation, by direct micro-injection into the ventrolateral periaqueductal gray[33] and alter trigeminothalamic dural-nociceptive traffic by microiontophoresis into the ventroposteromedial thalamic (VPM) nucleus.[79] It therefore is likely that triptans act on many neural sites to alter trigeminovascular nociceptive traffic, also with likely actions on peripheral meningeal nociceptors.[73] While sumatriptan is not considered to be brain penetrant, it is effective in the treatment of migraine. Whether it gains access to the brain, and specifically the TCC and other brain structures, is still to be determined. However, it is undoubtedly the case that lipophilic triptans can also affect central structures throughout the brain in areas thought to be important in migraine, and the TCC is an ideal and likely target for drug action in migraine therapy. A review of the possible sites of action of triptans can be found in Figure 1.

Figure 1.

Probable sites of action of triptans and calcitonin gene-related peptide receptor antagonists in the trigeminovascular system. Triptans are thought to have actions at 5-HT1B receptors located on dural meningeal and cerebral blood vessels, where activation is believed to cause vasoconstriction of blood vessels. Activation of 5-HT1D receptors, located on peripheral nerve fibers is thought to prevent the pre-junctional release of CGRP and subsequent vasodilation of dural meningeal arteries. Although whether these actions are relevant to their anti-migraine efficacy is debated. The location of 5-HT1B/1D/1F receptors on second-order neurons in the trigeminal nucleus, and the responses of iontophoresed triptans and 5-HT1F receptor agonists on L-glutamate and dural activated neurons imply potentially both pre- and postsynaptic modes of action on central neuronal transmission. Where their activation may prevent the presynaptic release of neuronal CGRP and/or postsynaptically inhibit activation of neurons. Triptans are also known to act on neurons in the ventrolateral periaqueductal gray to modulate trigeminovascular nociceptive traffic, and VPM nuclei in the processing of trigeminothalamic nociceptive responses. At the level of the periphery, CGRP receptor antagonists may act by preventing the vasodilatory actions of CGRP receptor activation by CGRP release on the smooth muscle. Centrally located CGRP receptors in the trigeminal nucleus are most likely postsynaptic, inhibiting activation of trigeminal second-order neurons. CGRP receptor antagonists are also known to have effects on neurons in ventrolateral periaqueductal gray to modulate trigeminovascular nociceptive traffic and trigeminothalamic nociceptive neurons of the ventroposteromedial thalamus.
CGRP: Calcitonin gene-related peptide; NKA: Neurokinin A; PACAP: Pituitary adenylate cyclase activating peptide; SP: Substance P.

Non-steroidal Anti-inflammatory drugs

NSAIDs as analgesics, such as acetaminophen, aspirin, ibuprofen, ketorolac, indomethacin and naproxen, are used routinely to treat migraine.[5,80] Their mechanism of action is generally as non-specific COX-1 and -2 inhibitors in the brain and vasculature, preventing the production of prostaglandins,[81] which may ultimately provoke a neuroinflammatory cascade response at the level of the cranial blood vessels, and potentially the TCC to increase neuronal activation in this region. However, they do exhibit some differences in their response as treatments and mechanism of action. A case in point is indomethacin, which appears to be specifically responsive to paroxysmal hemicrania and hemicrania continua,[82] and may potentially have a different mechanism of action via nitrergic mechanisms.[83] It is likely that only COX-2 inhibition, rather than COX-1, contributes to the reduction of prostaglandins in the brain and spinal cord to reduce pain.[84–86] Prostaglandin actions are mediated by a G-protein coupled family of prostaglandin or EP receptors, four of which have been classified (EP1–EP4). There is evidence of mRNA expression of EP1–EP4 receptors in the dural middle meningeal artery and middle cerebral artery, trigeminal ganglion and trigeminal nucleus caudalis (or TCC) in rats, with the greatest expression of EP2 and EP4 receptor mRNA in dural and cerebral arteries, followed by the trigeminal ganglion and TCC.[87] Furthermore, immunoreactivity to COX-1 and COX-2 isoforms in the dura mater has also been demonstrated.[88] COX-1 was found mainly in blood vessels, particularly meningeal, in the endothelium. COX-2 was found predominantly with macrophages and on axonal profiles, often co-localized with calcitonin gene-related peptide (CGRP), indicative of peripheral nociceptive nerve endings. In the clinical experimental setting in migraineurs, prostaglandin E2 (PGE2) can cause an immediate migraine-like headache in the majority of patients it is given to,[89] and there is evidence of PGE2 release within 1 h of migraine onset in jugular vein samples in patients.[90] Also prostaglandin I2 (PGI2) has been shown to produce headache and delayed migraine-like symptoms in a proportion of patients.[91] These data lead to the suggestion that COX-2 mechanisms via prostaglandin release may be involved in the pathophysiology of migraine, and using targeted COX-2 inhibitors at the trigeminovascular system is likely to provide the locus of action for pain relief. Although where in the trigeminovascular system they act is not completely clear.

In preclinical studies, PGE2 causes vasodilation of the middle meningeal artery in rats via systemic or topical application but not of middle cerebral artery and this response is mediated predominantly via activation of EP4 receptors, and to a lesser extent EP2 receptor activation.[87] Furthermore, PGE2 is part of the inflammatory soup that is used and placed on the dura mater to induce peripheral and central neuronal sensitization of TCC neurons in rats.[11] PGI2 has similarly been shown to produce peripheral sensitization of meningeal nociceptors in rats.[92] These data point to a conclusion that a peripheral, with both vascular and neurovascular, locus of action is a possible mechanism for providing relief as a therapeutic mechanism in migraine. Indeed, naproxen and indomethacin, non-specific COX inhibitors, which are effective in the treatment of migraine to differing degrees, were both effective at inhibiting sensitization of peripheral meningeal nociceptors.[93,94] While not definitive, as systemic administration was used in each case, it seems likely that they are acting, at least, at the level of the periphery, probably on meningeal nociceptors, to reduce trigeminovascular activation. COX inhibitors are also effective in other models of trigeminovascular nociceptive activation. Changes in diameter of the meningeal vessels[95] after electrical stimulation of the meninges (neurogenic dural vasodilation), or manipulation with chemical triggers of migraine, such nitric oxide (NO) donors[96,97] or CGRP[98] is also indicative of trigeminovascular activation. Indomethacin, naproxen and ibuprofen were all able to inhibit neurogenic dural vasodilation, however only indomethacin inhibited NO-induced dural vasodilation, and there was no effect on CGRP-induced vasodilation from each molecule.[99,100] These data imply that COX inhibitors are unlikely to be acting on the smooth muscle of vessels, but potentially act at the level of the endothelium or more likely trigeminal nerve endings and meningeal nociceptors to altered nociceptive traffic in the TCC.

However, similar to the triptan story, to some this does not readily fit into a hypothesized pathophysiology of migraine. It is likely to involve activation and sensitization of central trigeminovascular neurons, which may be triggered by a change in state of activation of brainstem and diencephalic nuclei that mediates this activation, or at the very least exacerbates and sustains trigeminovascular activation and sensitization.[6,7] Indeed, some regard the vascular changes that are sometimes evident during migraine an epiphenomenon,[101] and agents that provoke meningeal vasodilation in humans, do not exhaustively induce migraine, such as vasoactive intestinal peptide.[102] If this is the case then a centrally mediated locus of action, without action at the peripheral vasculature and its neural input, needs to be demonstrated. The first convincing data come from the Myren et al. study. They show that mRNA expression for the EP2 and EP4 receptors is present in the trigeminal ganglion, but more importantly also in the trigeminal nucleus. Furthermore, using the NO donor, glyceryl trinitrate, in an animal model shown to produce activation in brain areas active during migraine, including the TCC,[103] it has been demonstrated that COX-2 expression is increased in the hypothalamus after 2 h and in the lower brainstem, which includes the TCC, after 4 h.[104] PGE2 was also significantly increased in the lower brainstem after 4 h.[104] The data imply that changes to COX-2 and PGE2 levels in the brain, in areas thought to be involved in the premonitory symptoms and generation of migraine (hypothalamus), and an area that would include the TCC, are occurring with a chemical trigger of migraine. These data indicate that potentially targeting these areas with NSAIDs that inhibit COX-2 may prove effective in the treatment of migraine. Studies using electrophysiological recording of TCC neuronal activation in response to dural electrical stimulation may help provide the answer to this. Indeed, aspirin, indomethacin and naproxen[32,105,106] have all been shown to inhibit neuronal responses at the TCC, with systemic administration. Furthermore, naproxen is known to inhibit central sensitization of trigeminovascular neurons in rats.[107] Systemic indomethacin was further shown to inhibit NO-induced neuronal activation in the TCC.[83] Again, while these data imply an activity at the TCC they are not definitive. However, studies are ongoing that are trying to disseminate the locus of action of these NSAIDs, using microiontophoretic techniques, locally iontophoresing these molecules into the TCC. A positive response of NSAIDs at inhibiting neurons of the TCC in these studies would clearly demonstrate their mechanism of action in the TCC. Currently, the data seem to indicate that the actions of these COX inhibitors are likely to be neurally based, at the level of the periphery via the meningeal nociceptors, and electrophysiology data also imply an action in the brain, potentially at the level of the TCC, but sites in the brainstem and diencephalic nuclei, known to modulate trigeminovascular nociceptive traffic, could also provide a mechanism of action. These future studies will tell us more. An overview of the possible sites of action of NSAIDs can be found in Figure 2.

Figure 2.

Possible sites of action of topiramate and NSAIDs, via COX inhibition, in the trigeminovascular system. The site of action of topiramate and NSAIDs in the trigeminovascular is not clear, but certain actions have been hypothesized. Topiramate is thought to inhibit cortical activity to reduce aura symptoms in patients and block cortical spreading depression (CSD). Topiramate is known to act via various mechanisms including sodium and calcium ion channels, glutamatergic NMDA, AMPA and kainate receptors and via potentiation of GABAergic inhibition [133], mechanisms all known to block CSD in various animal models [204–206]. In the periphery, it is likely that topiramate, at least, acts on pre-junctional nerve fibers to inhibit calcitonin gene-related peptide release, possibly via L, N and P/Q-type VG calcium ion channels [207]. Similarly on central neurons, the actions of topiramate are likely to be via pre- and postsynaptic actions at L, N and P/Q-type VG calcium ion channels [208], postsynaptic kainate receptor inhibition [147] as well as actions at GABAA receptors [209]. Topiramate is also known to inhibit nociceptive trigeminothalamic neurons in ventroposteromedial thalamic nuclei. Furthermore, via actions on GABAergic mechanisms and P/Q-type VG calcium ion channels in the periaqueductal gray, topiramate may be able to modulate nociceptive activation of trigeminocervical complex (TCC) neurons.
NSAIDs are thought to act predominantly via COX-2 inhibition, inhibiting the production of prostaglandins (PG, PGE-2 and PGI-2) to exert their anti-migraine effects. Within the trigeminovascular system, NSAIDs may inhibit prostaglandin production at the level of the endothelium on meningeal blood vessels to prevent vasodilation of meningeal blood vessels. It is also likely that COX-2 inhibition prevents the release of CGRP and other neuropeptides to prevent meningeal vasodilation and sensitization of meningeal nociceptors. At central neurons, NSAIDs are known to inhibit trigeminal firing of neurons of the TCC, and this locus of action seems most likely to explain migraine efficacy. While their locus and mechanism of action at the TCC is not clear it seems likely the NSAIDs disrupt the communication of neurotransmission across the second-order synapse, via COX-2 inhibition, at both pre- and postsynaptic receptor loci. COX-2 immunoreactivity has been demonstrated at the caudal medulla where the TCC is, therefore COX inhibition would prevent the production of prostaglandins, and thus there is a lack of activation of EP2 and 4 receptors at this central neuron, reducing neuronal transmission. Furthermore, it is known that PGE2 levels are increased in the hypothalamus with a migraine trigger.
CGRP: Calcitonin gene-related peptide; VG: Voltage-gated.

Calcitonin Gene-related Peptide Receptor Antagonists

Small molecule CGRP receptor antagonists (gepants) are the newest class of acute anti-migraine therapy to really carry momentum and optimism for patients. A proof-of-concept clinical trial using olcegepant (BIBN4096BS)[108] demonstrated clear efficacy in the acute treatment of migraine. Subsequent studies with telcagepant (MK-0794),[109] MK-3207[110] and BI 44370 TA[111] have demonstrated the clinical efficacy of this class of drugs in the acute treatment of migraine. Unfortunately, their development to the market has been hampered by concerns over liver toxicity,[110,112] although this is thought to be an off target effect. CGRP as a molecule gained momentum for being potentially involved in the pathophysiology of migraine when it was found that levels were raised in the blood plasma of humans and cats after activation of the trigeminal ganglion.[113] Subsequently, it was found that levels of only CGRP were raised in the blood plasma of migraine patients during severe migraine[114] and levels were normalized with sumatriptan.[115] CGRP is also able to trigger a delayed migraine in migraineurs,[98] similar to NO donors. Furthermore, in animal models of trigeminovascular nociception, electrical stimulation of the dura mater also produces release of CGRP, without the release of substance P,[115,116] supporting the use of dural electrical stimulation as a preclinical assay to screen for therapeutics. Components of the CGRP receptor are known to be present at the level of the dural vasculature but not on peripheral sensory axons.[117] They are also found in the trigeminal ganglion and at the level of the TCC.

Preclinical studies clearly demonstrate that CGRP is a potent vasodilator of meningeal arteries, a response that is blocked by CGRP receptor antagonists.[118,119] Furthermore, meningeal vasodilation and increase in blood flow, as a consequence of electrical stimulation of the dural vasculature, is thought to be mediated by the release of CGRP from nerve terminals.[118,120,121] Systemic CGRP does not appear to have any direct effects on meningeal nociceptors, it does not sensitize dural mechanoceptors,[122] but it does facilitate vibrissal responses of TCC neurons.[123] These studies might imply that the effects of CGRP and its antagonists are less likely in the periphery. However, CGRP is a large peptide, unlikely to cross the blood–brain barrier, therefore central effects may be difficult to predict. However, the development of the small molecule CGRP antagonists has given way to potentially brain penetrant molecules that may have effects at the level of the TCC. Intravenous olcegepant is able to inhibit spontaneous discharge firing in the TCC, whereas topical dural application has no effect.[124] This would indicate that endogenous release of CGRP contributes to the maintenance of spontaneous firing in the TCC. In a microiontophoresis study, CGRP was locally iontophoresed onto TCC neurons, and caused bursts of firing similar to that found traditionally with L-glutamate in these studies.[125] This implies that local release of CGRP can cause further excitation of trigeminovascular neurons in the TCC. Iontophoretic application of the CGRP receptor antagonist, olcegepant, inhibited both spontaneous firing of TCC neurons and L-glutamate-induced firing, while intravenous administration caused a dose-dependent inhibition of dural-evoked neuronal firing in the TCC.[125] Combining these data imply that some action of CGRP receptor antagonists is likely to be at the level of the TCC, that some ongoing level of activity in the TCC is driven by local release of CGRP, in line with the study by Fischer et al. Finally, the local inhibition of glutamatergic excitation implies CGRP receptors are non-presynaptic, most likely postsynaptic. Similar to triptans, while a locus of action of CGRP antagonists in the TCC in patients cannot be confirmed, it seems less likely that actions at the level of the periphery would exert effects on the TCC, whereas direct actions at the TCC would make for an important therapeutic target. Actions in other areas of the brain cannot be discounted, as CGRP receptor antagonists, directly iontophoresed into the ventroposteromedial thalamus, inhibit dural trigeminothalamic nociceptive neurons.[126] An overview of the possible sites of action of CGRP antagonists can be found in Figure 1.

More recently, there has been a focus on the development of CGRP-related antibodies that have a longer half-life, and therefore more suitable for the preventive treatment of migraine.[127] In both skin and meningeal artery assays, electrical stimulation-evoked vasodilation was inhibited by the CGRP antibody similar to antagonists, with inhibition still detectable after 1 week of treatment,[127] with no detectable effect on heart rate or blood pressure. Another humanized CGRP antibody, LY2951742, has recently entered clinical trial for the treatment of migraine (Clinicaltrials.gov, NCT01625988). Other biological CGRP molecules developed for the treatment of migraine are the RNA-spiegelmer and the CGRP antibody, which specifically target scavenging CGRP.[128] These molecules were able to inhibit the effects of circulating CGRP on meningeal vasodilation, but did not inhibit electrical stimulation-evoked changes, caused by CGRP release from sensory nerve terminals. This may limit their efficacy in migraine. These biological approaches offer new avenues for the development of drugs that target the role of CGRP in the development of migraine. Where they target the effects of CGRP is still not clear, but the TCC remains an open possibility.

Topiramate

The anti-epileptics are a class of drugs that have proved very successful in the preventive treatment of migraine, and topiramate and sodium valproate have been the most studied preclinically, with most likely actions via GABAergic and glutamatergic mechanisms. This subject has been reviewed extensively elsewhere within Expert Reviews, therefore, the authors will concentrate on just one molecule as many of their mechanisms of action are similar, acting in the trigeminovascular system. Topiramate has proven to be very efficacious in the preventive treatment of migraine.[129–132] It is perhaps one of the most studied preclinically of the anti-epileptics used in the treatment of migraine, with pharmacological actions on voltage-gated sodium and calcium ion channels, and GABAergic and glutamatergic transmission.[133] Thus, it will be specifically focused on as a clear picture of its locus of action is realized throughout the brain and cranial vasculature. One of the advantages of topiramate is that it is used in the prevention of migraine, both with and without aura, effectively reducing aura symptoms. The exact role aura, and its believed experimental correlate, cortical spreading depression (CSD), have in the pathophysiology of migraine, have been discussed elsewhere in detail.[134–140] However, realizing that therapeutics have an effect in inhibiting CSD, which involves a wave of neuronal depolarization, induced by chemical or physical stimuli, which spread across the cortex at a similar speed to aura (2–6 mm/min) and is followed by a sustained hyperpolarization,[141,142] in animals models, helps us describe a locus of action at the level of the cortex. Topiramate has been demonstrated to inhibit needle prick induced CSD in both cats and rats, when given acutely.[143] It is also able to inhibit the number of CSD repetitions after KCl induction in rats, with chronic dosing for up to 17 weeks, but no response after only 1 week of dosing.[144] The data imply that topiramate is likely to have actions directly at the level of the cerebral cortex to reduce or inhibit CSD, and in essence effectively block or reduce the severity of aura in migraine.

While an action at the cortex seems logical to reduce the prevalence of migraine aura, it seems wholly unlikely that an action at purely cortical sites is responsible for preventing the occurrence of migraine pain, despite some theories that CSD and aura may be responsible for triggering trigeminovascular activation in migraine.[136,139] Indeed, intravenous topiramate is also highly effective in animal models of trigeminovascular nociception, inhibiting the effects of neurogenic dural vasodilation, as well as the effects of NO-induced dural blood vessel dilation, but not when the effect is driven by CGRP.[145] As described above, while it is thought CGRP acts on the smooth muscle of vessels to cause vasodilation, neurogenic dural vasodilation is thought to be a consequence of release of CGRP from the trigeminovascular pre-junctional nerve terminal. Similarly, NO may have some direct effects on endothelial cells of dural blood vessels, but also at the level of the nerve promoting CGRP release. It would seem unlikely that an action at the cortex is responsible for reducing these vascular changes, given the mode of action of the triggering mechanisms. More likely is that the effects of topiramate in these craniovascular models of trigeminovascular nociception are via inhibiting the presynaptic release of CGRP from pre-junctional nerve terminals, and thus attenuating vasodilation.

Again while the above data might imply mechanisms of action through logical conclusion, electrophysiological studies that use microiontophoresis can be more definitive about locus of action. Using electrophysiology and recording neuronal responses to dural electrical stimulation, intravenous administration of topiramate inhibits neuronal responses in the TCC in both cats[146] and rats,[147] as well neurons of the VPM nucleus in the rat.[147] These data imply a neuronal locus of action, potentially at the TCC and maybe even the VPM, although other sites of action cannot be discounted. However, iontophoretic data of neurons recorded in the TCC clearly demonstrate that topiramate is able to inhibit glutamatergic-activated responses of neurons that received dural nociceptive inputs, predominantly through kainate receptors.[147] The same study also demonstrates inhibitory responses of iontophoresed topiramate in the VPM as well. Finally, there is evidence that descending inhibitory modulation via the ventrolateral periaqueductal gray of dural-nociceptive trigeminovascular traffic is mediated by GABAergic mechanisms and P/Q voltage-gated calcium channels,[35,148] both likely pharmacological targets of topiramate. Collectively, these studies demonstrate that topiramate is most likely to have actions throughout the brain, including the cerebral cortex, TCC and likely via the ventrolateral periaqueductal gray that make it such an effective preventive treatment for migraine with and without aura. It seems hugely unlikely that effects solely at the level of the cortex are responsible for all the therapeutic benefits of topiramate and its modulation of trigeminovascular responses. With its known ability to cross the blood–brain barrier, and such definitive data that topiramate has a locus of action at the level of the TCC, the TCC seems a logical and important therapeutic target for topiramate in the preventive treatment of migraine, as well as other areas in the brain, including the cortex, brainstem and thalamic nuclei, which may mediate trigeminovascular nociceptive response. An overview of the possible sites of action of topiramate in the trigeminovascular system can be found in Figure 2

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