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. 

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Expert Commentary

After over 25 years of development of specific anti-migraine therapies, the migraineur is in a better place than they have ever been with potential avenues for how their migraine might be treated in the future. Yet with this optimism there is the knowledge that the migraineur is very much in the same position they were in when sumatriptan was first given market approval. At their disposal now are the over-the-counter medications, including NSAIDs, used for many pain disorders, and cheap generic versions of ergot derivatives and now triptans. Over-the-counter medications, like NSAIDs, are convenient for their availability, but are very much open to abuse and overuse because of this ease of access,[197,198] which can lead to the complication of more chronic forms of migraine and medication overuse headache. Even with the success of the triptans, all these current treatment options actually only help about 50% of sufferers. Therefore, safer and more effective treatments are needed to help those patients who do not respond to current treatments.

During these last few decades, our understanding of migraine's pathophysiology has also improved greatly, reviewed in detail elsewhere.[6–8] The introduction of the triptans into the clinic as a relatively specific anti-migraine drug[41] has provided researchers with a tool to be used to explore the pathophysiology of migraine further. Understanding the importance of the trigeminovascular system, and specifically neuronal targeting at the TCC, rather than using purely peripheral, vascular approaches, through our understanding of the mechanism of action of various triptans, has really moved on our understanding of migraine pathophysiology and improved the likely success of novel targets. The contrasting fortunes of the development of neurokinin 1 (NK1) receptor antagonists and extravasation inhibitors with that of some of the emerging targets, offer clear insight into the benefits of targeting the brain. The NK1 receptor antagonists and extravasation inhibitors were developed on the basis that migraine and activation of the trigeminovascular system is triggered by a sterile neurogenic inflammatory response at the level of the dura mater.[44] Animal models demonstrated neurogenic dural inflammation after stimulation of the trigeminal ganglion,[199] driven by the release of substance P, neurokinin A and CGRP,[113] is inhibited by sumatriptan and dihydroergotamine.[47,200] However, the subsequent development and failure of specific extravasation inhibitors[54,55] and NK1 receptor antagonists,[201,202] based on this hypothesis, has made it hard to sustain an argument that extravasation has a role in migraine pathophysiology and that simply targeting just the dura mater in this way will be effective. These data and the neurogenic inflammation hypothesis have been reviewed in detail recently.[203] By contrast, some of the emerging targets have been developed with the premise that targeting just the dural vasculature will not be sufficient for the treatment of migraine. These targets have been developed with a neuronal bias, where there must be effects on the neuronal portion of the trigeminovascular system, at the TCC, to have at least some success in the treatment of migraine. Indeed, in some cases, with 5-HT1F receptor agonists and glutamatergic targets, a purely neuronal mechanism of action has been the primary focus of their action and described as the mechanisms of their success in the clinic.

Developing therapeutic targets for migraine that are known to have direct effects on neurons of the TCC that receive inputs from the dural vasculature has proven to be a reliable way of screening novel potential anti-migraine molecules. CGRP receptor antagonists, 5-HT1F agonists, NOS inhibitors and several glutamatergic receptor targets, all of which are still in development, when demonstrated to be effective at inhibiting dural responsive neurons in the TCC, have also been found to be effective in the clinic. It has taken a long time for industry to realize the importance of investing in developing anti-migraine drugs that are able to get into the brain, and it is proven from preclinical studies through to the output in the clinic that this neuronal approach is likely to produce efficacious molecules, which can only benefit the patient. However, perhaps one needs to take a more global point of view to the development of therapeutics that can modulate trigeminovascular nociceptive traffic. It is clear from animal models of peripheral and central sensitization and dural trigeminovascular nociception that peripheral inputs into the TCC are important in the generation of migraine, but also that the mechanism that drives sensitization and the predisposition of migraineurs to develop migraine is quite probably driven from the brain. This demonstrates that both peripheral and central mechanisms are important. To be clouded by one specific mechanism may reduce the success of developing new entities that are effective and safe in all patients. Certainly, targeting the TCC has proven to be very effective in the treatment of migraine and needs to be continued, but other targets in the brain, such as areas of the pons and midbrain, areas of the hypothalamus and the thalamus and finally the cortex are also very important, and appear to be able to modulate how somatosensory inputs in the TCC are perceived. These are areas that seem to be able to modulate trigeminovascular nociceptive transmission, they are responsible for many of the non-painful neurological symptoms of migraine, they are also likely involved in the triggering of migraine, and therefore nuclei in these areas need to be considered, and responsive to novel treatment approaches. Finally, let us not forget that sumatriptan was developed for its effects on the peripheral dural vasculature. This is still an important area that needs to be considered in the development of novel targets, certainly for vascular contraindications, but also because the dural vasculature is richly innervated by trigeminal nociceptive nerve fiber that send signals to the TCC. Perhaps considering all these factors, and using preclinical screening that assay peripheral and central trigeminovascular components of activation and sensitization, and aspects of cortical activation, at the least, will produce more reliable molecules, rather than being blinded by one mechanism. It is hoped that the continued investment of the commercial sector in these targets, as well as the continued investment of researchers and industry together to create further novel approaches for treating migraine, will ultimately result in safer and more effective treatments reaching patients. The 50% of those patients who are unresponsive to the existing treatments can only benefit from this crucial investment.

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