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

Simon Akerman; Marcela Romero-Reyes


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

In This Article

Emerging Target

The importance of targeting the trigeminovascular system and particularly the observation of responses at the level of the TCC is demonstrated in the way emerging targets are screened in preclinical animal models and the relative degree of their success. There are several clear examples that might predict success in the clinic, these include 5-HT1F receptor agonists, modulation of the glutamatergic system, orexinergic system and nitrergic mechanisms.

5-HT1F Agonists

The pharmacology of many of the triptans described in the clinic have agonist activities beyond 5-HT1B/1D receptors, and very often includes the 5-HT1F receptors too.[149] While 5-HT1F receptors do appear to be present on vascular tissue, it seems that activation of this receptor does not cause vasoconstriction of human cerebral and meningeal arteries, or coronary arteries.[46,150] 5-HT1F receptors are also clearly present on human and rat trigeminal ganglia cells[151,152] and there is mRNA expression in rat and guinea pig spinal trigeminal nucleus,[153,154] implying expression in the TCC. Therefore, the 5-HT1F receptor agonists may represent a clinical target without the cardiovascular indications that affect triptans, and a potential mechanism of action on purely neural sites that would fit with the perceived central hypothesis of migraine. Furthermore, preclinical studies would seem to predict success in the clinic and they have been able to help dissect their potential locus of action. In the neurogenic dural inflammation assay in both rats and guinea pigs, various selective 5-HT1F agonists (LY344864, LY334370 and LY573144) inhibit dural extravasation after trigeminal ganglion stimulation.[155–157] Likewise after trigeminal ganglion, stimulation in rats 5-HT1F agonists (LY334370 and LY573144) inhibit the level of c-Fos immunoreactivity, a marker of neuronal activation, in the trigeminal nucleus caudalis,[157] the rostral portion of the TCC. In a similar assay that uses intracisternal capsaicin injection to activate neurons in the trigeminal nucleus, LY344864, also inhibited c-Fos immunoreactivity in the trigeminal nucleus caudalis in both mice and rats.[158,159] These data indicate that these compounds may be inhibiting at both the neuromuscular junction to the dura mater and neurotransmission to the nucleus caudalis. In studies that use dural electrical stimulation, LY344864 (common carotid blood flow) and LY334370 (neurogenic dural vasodilation) have no effect on craniovascular changes in cat[160] and rat,[161] respectively, which might imply the action at the neuromuscular junction is unlikely. However, electrophysiological neuronal responses in the TCC after dural electrical stimulation are significantly inhibited by 5-HT1F agonists in the cat[160] and rat.[161] These data again imply a neural basis for therapeutic action of 5-HT1F agonists and most likely at the TCC. Indeed, more recent studies using microiontophoresis confirm a direct action on TCC neurons. Locally iontophoresed LY344864 in the TCC significantly inhibited glutamatergic responsive TCC neurons, as well as dural electrical evoked and cutaneous facial receptive field responses in the TCC.[162] A clear action of this 5-HT1F agonist at the TCC is demonstrated, and the TCC would be considered the likely clinical target for the treatment of migraine with this class of molecules.

In the original double-blind, placebo-controlled clinical trial, LY334370 demonstrated effectiveness in acute migraine, but the molecule was hampered by CNS side effects at doses that produced efficacy.[163] This target has been revisited with lasmitidan (COL-144; LY573144) and again has shown excellent clinical efficacy for acute migraine in double-blind, placebo-controlled trials, and was well tolerated, with similar but less severe side effects.[164,165] It seems clear that the 5-HT1F receptor is a very useful emerging target in the treatment of migraine. It represents a purely neuronal rationale given the abundance of preclinical data, and further supports the central hypothesis of migraine. While other brain areas cannot be discounted at this stage, which modulate trigeminal responses, as the volume of preclinical research conducted does not come close to that of the triptans yet, however, the TCC is a very likely target for their therapeutic action, as summarized in Figure 1.

Glutamatergic Receptor Targets

More recently other pharmacological strategies have emerged with the potential for development as a consequence of purely neuronal approaches, with effects on neurons in the TCC. Glutamate and glutamatergic targets have long been associated with migraine and represent a neuronal-specific approach.[166] NMDA, with MK-801, and AMPA, with GYKI52466, receptor antagonists are effective at inhibiting trigeminovascular nociceptive transmission at the level of the TCC.[167–169] Memantine, which targets the magnesium binding site of the NMDA receptor, has been proven to be effective in the preventive treatment of migraine in several retrospective studies.[170] Also the iGluR5 subunit of the kainate receptor is involved in the modulation of trigeminovascular nociceptive traffic,[171,172] as well being a key component in the effects of topiramate in the modulation of both TCC and VPM neurons.[147] Furthermore, a specific iGluR5 subunit antagonist, LY466195, was effective at inhibiting trigeminal ganglion stimulation induced dural plasma extravasation, as well as c-Fos immunoreactivity in the trigeminal nucleus caudalis.[173] This same molecule was also effective in the acute treatment of migraine, although with some visual side effects,[174] as was the AMPA/kainate receptor antagonist, LY293558.[175] These data provide support for further development of neuronal glutamatergic targets in the therapeutic treatment of migraine.

Orexinergic System

The orexinergic system is relatively new in its association with the treatment of migraine. It includes two neuropeptides, orexin A and orexin B, made solely in the hypothalamus and they have an involvement in the hypothalamic regulation of feeding, arousal and the autonomic system.[176] There is evidence of altered levels of orexins in the more chronic forms of migraine and headache.[177] They target the orexin 1 and 2 receptors, which are known to be present in the spinal trigeminal nucleus, with orexin A acting on both 1 and 2 receptors, but orexin B acting preferentially on orexin 2 receptors.[176] Preclinical studies demonstrate that systemic orexin A preferentially inhibits trigeminovascular nociception at both peripheral and central neural projections using neurogenic dural vasodilation[178] or electrophysiological recording at the TCC,[179] respectively. These data demonstrate orexin A is likely to have its effects at the neural projections of both peripheral and central aspects of the trigeminovascular system to modulate trigeminovascular activation. Orexin B had little effect on either vascular or neuronal components of the trigeminovascular system. Interestingly, when orexin A and B are microinjected into the posterior hypothalamus, these molecules have differential effects on dural and cutaneous-evoked inputs to the TCC. Orexin A inhibits responses in the TCC to dural electrical and thermal facial cutaneous inputs, whereas orexin B microinjection increased these responses.[37] While the data are not definitive, they certainly imply that targeting the orexin receptors in the TCC in the treatment of migraine potentially may be therapeutic. These data also suggest that targeting orexinergic receptors in other areas of the brain may modulate trigeminovascular nociceptive traffic. There have been no clinical trials conducted for migraine with respect to treatment with orexinergic molecules of any kind, however there are at least two (almorexant and suvorexant) orexinergic molecules that exist that have been involved in clinical studies for sleep disorders and/or safety and tolerability.[180–183] These data demonstrate that the potential is there for the development of novel molecules for this emerging target area.