Targeting the Trigeminocervical Complex in Migraine
It is hoped that continued investment with at least one of the above emerging and novel targets will result in new medications reaching the patients who can treat their acute migraine. However, one area of treatment that struggles to make the same breakthrough is the development of migraine-specific targets for the preventive treatment of migraine. It is a sad fact for the migraineur that of the existing preventive treatments used not one is a consequence of a targeted development program with migraine as a primary indication. They are often discovered serendipitously with an alternate primary disease target. Perhaps, this is a consequence of a lack of adequate animal models for preventive screening, or that our understanding of the pathophysiology of the more chronic forms of migraine is not as developed as episodic migraine, although there are examples of successful responses in animal models. Using animal models of CSD shows that preventives can attenuate responses, although it is unlikely that this highlights an effect on the trigeminovascular system or the headache component in migraine. Topiramate has been proven to be very effective in many models of trigeminovascular nociception, and neurons of the TCC are clearly an effective target. It is likely that industry will turn its focus to developing preventive treatment strategies of migraine over the next 5 years and we may see some breakthroughs. It is important from the outset that the characteristics of the type of molecule and its anatomical target are well defined. The authors have discussed above that the development of molecules that act at different levels of the nervous system may be necessary. Migraine is a neurological disorder, so brain penetrant drugs make good sense. Certainly, the TCC as a relay between the sensory nociceptive information that travels from the head and face to the pain processing centers in the brain is crucial. Drugs also acting at other brain sites, such as nuclei in the pons, midbrain, diencephalon and as far as the cortex are more likely to provide global relief for patients. Lastly, drugs that act on the neural input to the dural vasculature are likely to aid in providing relief from certain qualities of migraine pain. While not all of these targets may be reached, or indeed safely, with the development of a novel target, being aware of the importance of targeting multiple central and peripheral sites is likely to improve the efficacy of any developed drug. What is also necessary and will require attention is to adapt the existing animal models. Most animal models generally assay one or two components of migraine pathophysiology, and certainly none completely model the complexity of migraine. Most researchers favor one approach over another, and very often find themselves blinkered to other assays of merit. If novel targets are to be developed they need to be tested in preclinical assays that model as many aspects of migraine as possible, including activation of dural nociceptive inputs, peripheral and central sensitization, descending manipulation of trigeminovascular nociceptive transmission, cortical spreading depression and using known clinical triggers of migraine. Most likely some of these assays need to be adapted so they more fully represent migraine as a syndrome, and exhibit more symptoms or activate more pathways related to migraine. To fully determine if a drug will be useful it needs to be fully tested appropriately otherwise the likelihood of failure will increase. Then with investment from industry and research funding bodies provided, perhaps the development of better and more accurate models, and appropriate validation with current and then novel molecules, some of these emerging targets may reach the patients who need them. It is also hoped that over the next 5 years there will be a better understanding of the brain areas that are involved in all aspects of migraine that perhaps help us understand the triggering of migraine, why it can be so prolonged and what happens to transform migraine from acute to chronic. Understanding more about migraine pathophysiology may generate more areas of the brain that have potential to be targeted by therapeutics. We know already that the most successful anti-migraine drug class, the triptans, act in the ventrolateral periaqueductal gray and the ventroposteromedial thalamus as well peripheral and central trigeminovascular neurons to potentially exert their effects. Certainly, the development of drugs that have wider reach in the brain and its peripheral projections seem likely to be more effective than a lone target. Whichever way is approached, to return to the original premise of this review, developing brain penetrant molecules, that target the TCC, as well as other brain targets such as specific nuclei of the brainstem, hypothalamus and thalamus, which can modulate nociceptive responses in the TCC, will likely be the most fruitful method in predicting the clinical therapeutic efficacy of novel targets.
Five-year View
It is hoped that continued investment with at least one of the above emerging and novel targets will result in new medications reaching the patients who can treat their acute migraine. However, one area of treatment that struggles to make the same breakthrough is the development of migraine-specific targets for the preventive treatment of migraine. It is a sad fact for the migraineur that of the existing preventive treatments used not one is a consequence of a targeted development program with migraine as a primary indication. They are often discovered serendipitously with an alternate primary disease target. Perhaps, this is a consequence of a lack of adequate animal models for preventive screening, or that our understanding of the pathophysiology of the more chronic forms of migraine is not as developed as episodic migraine, although there are examples of successful responses in animal models. Using animal models of CSD shows that preventives can attenuate responses, although it is unlikely that this highlights an effect on the trigeminovascular system or the headache component in migraine. Topiramate has been proven to be very effective in many models of trigeminovascular nociception, and neurons of the TCC are clearly an effective target. It is likely that industry will turn its focus to developing preventive treatment strategies of migraine over the next 5 years and we may see some breakthroughs. It is important from the outset that the characteristics of the type of molecule and its anatomical target are well defined. The authors have discussed above that the development of molecules that act at different levels of the nervous system may be necessary. Migraine is a neurological disorder, so brain penetrant drugs make good sense. Certainly, the TCC as a relay between the sensory nociceptive information that travels from the head and face to the pain processing centers in the brain is crucial. Drugs also acting at other brain sites, such as nuclei in the pons, midbrain, diencephalon and as far as the cortex are more likely to provide global relief for patients. Lastly, drugs that act on the neural input to the dural vasculature are likely to aid in providing relief from certain qualities of migraine pain. While not all of these targets may be reached, or indeed safely, with the development of a novel target, being aware of the importance of targeting multiple central and peripheral sites is likely to improve the efficacy of any developed drug. What is also necessary and will require attention is to adapt the existing animal models. Most animal models generally assay one or two components of migraine pathophysiology, and certainly none completely model the complexity of migraine. Most researchers favor one approach over another, and very often find themselves blinkered to other assays of merit. If novel targets are to be developed they need to be tested in preclinical assays that model as many aspects of migraine as possible, including activation of dural nociceptive inputs, peripheral and central sensitization, descending manipulation of trigeminovascular nociceptive transmission, cortical spreading depression and using known clinical triggers of migraine. Most likely some of these assays need to be adapted so they more fully represent migraine as a syndrome, and exhibit more symptoms or activate more pathways related to migraine. To fully determine if a drug will be useful it needs to be fully tested appropriately otherwise the likelihood of failure will increase. Then with investment from industry and research funding bodies provided, perhaps the development of better and more accurate models, and appropriate validation with current and then novel molecules, some of these emerging targets may reach the patients who need them. It is also hoped that over the next 5 years there will be a better understanding of the brain areas that are involved in all aspects of migraine that perhaps help us understand the triggering of migraine, why it can be so prolonged and what happens to transform migraine from acute to chronic. Understanding more about migraine pathophysiology may generate more areas of the brain that have potential to be targeted by therapeutics. We know already that the most successful anti-migraine drug class, the triptans, act in the ventrolateral periaqueductal gray and the ventroposteromedial thalamus as well peripheral and central trigeminovascular neurons to potentially exert their effects. Certainly, the development of drugs that have wider reach in the brain and its peripheral projections seem likely to be more effective than a lone target. Whichever way is approached, to return to the original premise of this review, developing brain penetrant molecules, that target the TCC, as well as other brain targets such as specific nuclei of the brainstem, hypothalamus and thalamus, which can modulate nociceptive responses in the TCC, will likely be the most fruitful method in predicting the clinical therapeutic efficacy of novel targets.
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