Abstract
Migraine is a highly disabling neurological disorder, with a prevalence of 15-18% worldwide, with a significantly higher incidence in women over men. It is characterised by a periorbital throbbing pain, together with a set of sensory disturbances; known as the premonitory phase, which can start up to 72 hours prior to the pain, and remain up to 48 hrs after pain resolution (postdrome phase). Clinical imaging data has shown central structures such as the hypothalamus and the locus coeruleus to be altered throughout the premonitory phase and in between attacks during resting conditions.Orexinergic networks emerging from the lateral hypothalamus have demonstrated a differential modulatory action over migraine-associated nuclei such as the trigeminocervical complex in in vivo anaesthetised animal models. In this project we sought to further investigate the role of the orexinergic system in the regulation of trigeminal nociception and migraine-related symptoms using cre-dependent AAVapproaches. We observed a significant decrease in periorbital mechanical withdrawal thresholds in orexin-ablated mice, which is reflective of a sensitisation of the trigeminovascular system. This sensitisation was normalised by chronic intranasal orexin A, while further studies identified a potential mechanism of action of orexin A acting via the orexin 1 receptors in the locus coeruleus.
Downstream from the hypothalamus; orexinergic projections are known to densely innervate the locus coeruleus, which is the main source of noradrenaline in the central nervous system. Given the potential action of orexin A via the locus coeruleus and its ability to modulate trigeminal nociception we next sought to optimise a novel retrograde canine-adenovirus 2 (CAV2) vector to permit chemogenetic activation of locus coeruleus noradrenergic neurons in freely behaving rats. Clozapine-N-oxide-mediated activation of these noradrenergic neurons inhibited trigeminal nociception, while pilot work in awake rats highlighted increased mechanical withdrawal thresholds following locus coeruleus activation.
Together, the data in this thesis highlights the potential importance of hypothalamic orexinergic and locus coeruleus noradrenergic mechanisms in trigeminal nociception and migraine associated symptomatology (premonitory symptoms). Our data specifically highlights the therapeutic potential of orexin A, targeted activation of the orexin 1 receptor and noradrenergic signalling as potential therapeutic strategies that have the potential to modulate migraine-related neural circuits likely responsible for increased attack susceptibility.
| Date of Award | 1 Jun 2022 |
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| Original language | English |
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| Supervisor | Philip Holland (Supervisor), Peter Goadsby (Supervisor) & Samuel Cooke (Supervisor) |