Abstract Details

Title Dual Orexin Receptor Antagonist 12 Represses Expression of Proteins in Neurons and Glia Implicated in Peripheral and Central Sensitization

Topic Headache

Presentation(s) P06 - (-)

Poster/Presentation
Number 158

Objective

Background BACKGROUND: Trigeminal activation is implicated in migraine pathology and data from clinical studies support a significant relationship between sleep quality and migraine. Orexins regulate sleep-awake patterns in humans and clinical studies have shown promise for orexin antagonists restoring sleep architecture. Furthermore, sleep is considered an effective means for alleviating pain associated with migraine.

Design/Methods DESIGN/METHODS: We measured changes in nocifensive behaviors and utilized immunohistochemistry to study changes in proteins implicated in peripheral and central sensitization in trigeminal ganglia and spinal trigeminal nucleus in male Sprague Dawley rats. Rats were injected with complete Freunds adjuvant (CFA) in the orofacial region to promote activation of trigeminal neurons. Some rats received daily oral administration of DORA-12 and a single injection with CFA. Mann-Whitney U was used to determine statistical significance.

Results RESULTS: Initially, we found that treatment with DORA-12 repressed nocifensive behaviors in response to mechanical stimulation of trigeminal nerves in REM sleep deprived rats. Using immunohistochemistry, both orexin R1 and R2 were found to be expressed in ganglia and spinal cord tissue. Rats receiving CFA injections exhibited increased expression of P-p38, and Iba1 in trigeminal ganglia and P-ERK, P-p38, and Iba1 in spinal trigeminal nucleus at 2 days post injection. However, the levels of P-ERK, P-p38, and Iba1 in rats receiving daily DORA-12 were repressed to near basal levels.

Conclusions CONCLUSIONS: Results from this study provide evidence that DORA-12 administration can repress trigeminal neuron and glial activation associated with development of peripheral and central sensitization, and thus orexin dual receptor antagonists may be useful as a therapeutic option for migraine and other diseases involving trigeminal nerve activation.

Authors/Disclosures
Paul L. Durham, PhD (Missouri State University) PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
Augusto Grinspan, MD (Acorda Therapeutics, Inc.)	Dr. Grinspan has received personal compensation for serving as an employee of Insightec.

��ɫ��

��ɫ��