Insights into the pharmacological targeting of the trigeminocervical complex in the context of treatments of migraine

Migraine is one of the most severe and debilitating brain disorders. Most scientists accept that it involves activation and sensitization of the trigeminovascular system, which includes the sensory peripheral projections to the pain-producing dura mater, and a central projection to the trigeminal nucleus caudalis and its cervical extension, the trigeminocervical complex (TCC). The development of the anti-migraine therapeutics, triptans-5-HT1B/1D receptor agonists, had originally targeted the craniovasculature to exert therapeutic effects, and this locus of action seemed to predict efficacy in the clinic. However, subsequent development of novel targets, using the same strategy failed to replicate this early success and as a consequence central mechanisms of action away from the dural vasculature were thought to be responsible for these therapeutic effects. Coupled to this, migraine has been hypothesized to involve a dysfunction of areas of the brainstem and diencephalon, which seem to mediate the activation, or perception of activation, of the trigeminovascular system as well as sensitization of neuronal pathways that drive trigeminovascular activation. Therefore, drug targets that act in the brain, specifically on the central component of the trigeminovascular system, the TCC, would seem to be ideally placed to modulate this nociceptive pathway and relieve migraine, but particularly the headache phase. This review will discuss how the TCC, rather than other more craniovascular sites, may be the anatomical target of some of the current and emerging therapies to relieve migraine symptoms, and why this should prove to be a fruitful area for drug development for the treatment of migraine.