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

Abstract

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-HT_1B/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.

Keywords::

• brainstem
• CGRP receptor antagonists
• migraine
• NSAIDs
• preventives
• trigeminocervical complex
• triptans

Financial & competing interests disclosure

S Akerman has consulted over the last 3 years for, advised and collaborated with Allergan, MAP Pharmaceuticals and MSD, and was an employee of Eli-Lilly Co. Ltd. from 2009 to 2011. M Romero-Reyes has received research funding from MSD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Migraine is a severe and debilitating disorder of the brain.

• • It is thought to involve activation of both peripheral and central aspects of the trigeminovascular system.

• • The convergent inputs to the central projection of the trigeminovascular system, the trigeminal nucleus caudalis and the C1 and C2 regions of the spinal cord, collectively known as the trigeminocervical complex (TCC) is thought to explain the common distribution of pain in migraine.

• • Drugs that target the TCC and inhibit neuronal activity in this region are thought to increase the likelihood of being clinically efficacious.

• • Established acute therapies, such as the ‘triptans’-5-HT_1B/1D receptor agonists, NSAIDs COX inhibitors and calcitonin gene-related peptide antagonists, and the preventive treatments anti-epileptics, including topiramate, have been demonstrated to have actions at the TCC in preclinical studies, and this is likely to be one of the targets of the therapeutic effects of these drugs.

• • Emerging targets, such as 5-HT_1F agonists, glutamatergic antagonists been developed as a purely neuronal approach, with actions at the TCC that would predict, and have been subsequently validated in the clinic, as being effective in the treatment of migraine.

• • Developing novel targets that have mechanisms of action at both peripheral and central projections of the trigeminovascular system, with demonstrated specific actions at the TCC, but other potential brainstem and diencephalic nuclei, will lead to increased likelihood of efficacy in the treatment of migraine.

Notice of correction

The original online publication of this article (16th August 2013) contained incorrect versions of the figures. These have been updated in the current version.

Notes