Abstract Details

Title Dual Orexin Receptor Antagonists Inhibit Nociceptive Neuronal Activity in the Trigeminocervical Complex of the Rat

Topic Headache

Presentation(s) S55 - (-)

Poster/Presentation
Number 006

Objective

Background The orexinergic system provides a pathway through which the hypothalamus can influence processes, such as the sleep wake cycle and nociceptive processing, via excitatory and inhibitory effects of orexin peptides. Experimental studies in rats have demonstrated that orexin A, which activates Ox1 and Ox2 receptors, is able to inhibit stimulus-evoked neuronal activity in the trigeminocervical complex (TCC), and orexin B, which activates Ox2 receptors, has pronociceptive properties. Such approaches do not differentiate exogenous effects from endogenous tone changes in orexinergic activity, which may be better addressed by investigating the effects of orexin receptor antagonists in models relevant to primary headache disorders.

Design/Methods Sprague-Dawley rats were anesthetized with pentobarbital (60 mgkg-1) and cannulated for physiological monitoring, maintenance of further anesthesia with intravenous propofol (20-25 mgkg-1h-1) and drug administration. A cranial window was prepared over the middle meningeal artery (MMA) and a bipolar electrode was placed on the dura mater above the MMA for electrical stimulation. For recording of neuronal activity a tungsten electrode was introduced in the TCC. Following intravenous administration of DORA-12 (1 mgkg-1) or its vehicle (25% hydroxypropyl-beta-cyclodextrin) stimulus-evoked and background activity were recorded over 60 minutes.

Results DORA-12 significantly inhibited stimulus-evoked neuronal activity in the TCC (-31.08±5.63 %, p = 0.002, n = 7) when compared against baseline. Vehicle control did not have a significant effect on neuronal activity (p = 0.201, n = 6). DORA-12 or vehicle control did not affect spontaneous background activity.

Conclusions The results show in an in vivo model of nociceptive trigeminovascular activation that dual orexin receptor antagonism reduces neuronal activity. The results support testing such compounds in migraine and cluster headache.

Authors/Disclosures
Jan Hoffmann, MD, PhD (Basic and Clinical Neuroscience, IoPPN, King's College London) PRESENTER	Dr. Hoffmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Chordate Medical AB. Dr. Hoffmann has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Chordate Medical AB. Dr. Hoffmann has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eli Lilly. Dr. Hoffmann has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Autonomic Technologies (ATI). Dr. Hoffmann has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Hoffmann has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva. Dr. Hoffmann has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hormosan Pharma. Dr. Hoffmann has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Allergan. Dr. Hoffmann has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Hoffmann has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Teva. Dr. Hoffmann has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for MD-Horizonte. Dr. Hoffmann has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Sage Publishing. Dr. Hoffmann has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Quintessence Publishing. The institution of Dr. Hoffmann has received research support from The Migraine Trust. The institution of Dr. Hoffmann has received research support from Celgene Corporation/Bristol Myers Squibb. Dr. Hoffmann has received publishing royalties from a publication relating to health care. Dr. Hoffmann has a non-compensated relationship as a Council Member with British Association for the Study of Headache that is relevant to AAN interests or activities. Dr. Hoffmann has a non-compensated relationship as a Board Member with Deutsche Migraene- und Kopfschmerzgesellschaft - DMKG -(German Migraine and Headache Society) that is relevant to AAN interests or activities.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Richard Hargreaves, PhD	No disclosure on file
Peter Hedera, MD (Vanderbilt University)	Dr. Hedera has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Hedera has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. Dr. Hedera has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for University of Louisville.
Peter Goadsby, MD, PhD, FRS (University of California, Los Angeles)	Dr. Goadsby has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Abbvie. Dr. Goadsby has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Eli-Lilly. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Aurene. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva Pharmaceuticals. Dr. Goadsby has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lundbeck. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Satsuma. Dr. Goadsby has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Pfizer. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Shiratronics. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for CoolTech LLC. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Linpharma. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PureTech Health LLC. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vial. Dr. Goadsby has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Aeon Biopharma. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Massachusetts Medical Society. The institution of Dr. Goadsby has received research support from NIHR. The institution of Dr. Goadsby has received research support from Kallyope. Dr. Goadsby has received publishing royalties from a publication relating to health care. Dr. Goadsby has received publishing royalties from a publication relating to health care. Dr. Goadsby has a non-compensated relationship as a Trustee with Migraine Trust that is relevant to AAN interests or activities. Dr. Goadsby has a non-compensated relationship as a Trustee with Organisation for Understanding Cluster Headache (UK) that is relevant to AAN interests or activities. Dr. Goadsby has a non-compensated relationship as a Executive roles with American Headache Society that is relevant to AAN interests or activities.

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