Thèse de doctorat en Sciences Biologiques et Médicales
Sous la direction de Lénaïc Monconduit.
Soutenue le 06-12-2017
à Clermont Auvergne , dans le cadre de École doctorale des sciences de la vie, santé, agronomie, environnement (Clermont-Ferrand) , en partenariat avec Neuro-dol (laboratoire) .
Le président du jury était Daniel Voisin.
Le jury était composé de Maud Gaëlle Frot.
Pathophysiological involvement of the Locus Coeruleus in migraine
Twelve percent of the world population suffers from migraine and its cost is estimated at 18 billion dollars per year in Europe. The frequency of attacks may increase over time in some migraineurs, evolving from episodic migraine (0 to 14 days of migraine/month) to chronic migraine (more than 15 days of migraine/month). Propranolol is one of the major prophylactic treatments of migraine, used to decrease the frequency of the attacks. However, its mechanism of action is largely unknown. Thus, using an animal model of repeated chemical stimulation of the dura, along with behavioural, electrophysiological, and immunohistochemical approaches, we assessed the prophylactic effect of per os propranolol on central sensitisation. It was able to prevent (i) the aggravation and persistence of central sensitisation as well as (ii) the alteration of descending controls of pain (iii) dural stimulation-induced activation of the locus coeruleus (LC). Recording simultaneously from Sp5C and LC then allowed us to demonstrate that (iv) LC integrates both cutaneous and meningeal nociceptive information and (v) LC exerts a facilitatory effect on Sp5C excitability, while in pathological conditions, (vi) integration of trigeminal nociception by LC was decreased while (vii) the modulation of Sp5C by LC was altered. We then tested the effect on central sensitisation of propranolol microinjection in the LC. It (viii) prevented central sensitisation but (ix) couldn’t reverse it. Finally, we investigated the mechanism of action of propranolol in the LC; the results suggested that (x) propranolol alters intrinsic properties of LC, thereby dampening its ability to facilitate Sp5C. In conclusion, our results revealed the facilitatory influence of the LC on trigeminal nociception, suggesting that the LC could play a facilitating role in triggering migraine headaches.
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