A translational in vivo model of trigeminal autonomic cephalalgias: therapeutic characterization.
Trigeminal autonomic cephalalgias are highly disabling primary headache disorders, characterized by severe unilateral head pain and associated ipsilateral cranial autonomic features. There is limited understanding of their pathophysiology and how and where treatments act to reduce symptoms; this is significantly hindered by a lack of animal models. We have developed the first animal model to explore trigeminal autonomic cephalalgias, using stimulation within the brainstem, at the level of the superior salivatory nucleus, to activate the trigeminal autonomic reflex arc. Using electrophysiological recording of neurons of the trigeminocervical complex and laser Doppler blood flow changes around the ipsilateral lacrimal duct, superior salivatory nucleus stimulation exhibited both neuronal trigeminovascular and cranial autonomic manifestations. These responses were specifically inhibited by the autonomic ganglion blocker hexamethonium bromide. These data demonstrate that brainstem activation may be the driver of both sensory and autonomic symptoms in these disorders, and part of this activation may be via the parasympathetic outflow to the cranial vasculature. Additionally, both sensory and autonomic manifestations were significantly inhibited by highly effective treatments for trigeminal autonomic cephalalgias, such as oxygen, indomethacin and triptans, and some part of their therapeutic action appears to be specifically on the parasympathetic outflow to the cranial vasculature. Treatments more used to migraine, such as naproxen and a calcitonin gene-related peptide receptor inhibitor, olcegepant, were less effective in this model. This is the first model to represent the phenotype of trigeminal autonomic cephalalgias and their response to therapies, and indicates the parasympathetic pathway may be uniquely involved in their pathophysiology and targeted to relieve symptoms.
Headache Group, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA. akermans@neurology.ucsf.edu
Simon
S
Akerman
Philip R
PR
Holland
Oliver
O
Summ
Michele P
MP
Lasalandra
Peter J
PJ
Goadsby
D000200:Action Potentials / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004599:Electric Stimulation Therapy / Q000379:methods*; D007839:Functional Laterality; D005730:Ganglionic Blockers / Q000494:pharmacology; D018738:Hexamethonium / Q000494:pharmacology; D007796:Laminectomy; D017078:Laser-Doppler Flowmetry; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000469:parasitology / Q000502:physiology; D010100:Oxygen / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D051303:Trigeminal Autonomic Cephalalgias / Q000209:etiology / Q000473:pathology / Q000628:therapy; D014278:Trigeminal Nuclei / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014363:Tryptamines / Q000494:pharmacology
D005730:Ganglionic Blockers; D010880:Piperidines; D058825:Serotonin 5-HT1 Receptor Agonists; D014363:Tryptamines; D018738:Hexamethonium; C106783:naratriptan; D010100:Oxygen