The (R)- isomer of isometheptene decreases trigeminal sensitivity in a rat model of primary headache

Introduction Isometheptene is thought to be the active ingredient of the commonly known headache medication, Midrin. Previously, we found only the (R) enantiomer to be effective in alleviating headache behavior in two models of headache compared to the (S) enantiomer. Experiments using electrical and mechanical stimulation of the dura in animals with no history of head pain have been used to elucidate the mechanisms of the trigeminovascular system at the level of the trigeminal ganglion, trigeminal nucleus caudalis, periaqueductal gray, and the thalamus. The limitation of these acute models is that electrical and mechanical stimulation of the dural blood vessels does not cause long lasting pain similar to recurrent headache pain in humans. Two animal models for the investigation of headache pathophysiology that include aspects of the chronic nature of headache were included in this study. These models provide a new approach to study the pathophysiology of recurrent headache and support validation of novel treatments. Using behavior methods of monitoring trigeminal allodynia in rats, our group discovered a rat with spontaneous episodic trigeminal allodynia (STA) (Oshinsky et al, 2012). The model was established through 18 generations of inbreeding for testing analgesics and the further understanding of mechanisms of migraine. STA rats experience similar symptoms to human migraine patients, such as episodic trigeminal sensitivity, phonophobia, responsiveness to abortive and prophylactic headache treatments, and sensitivity to migraine triggers. A second well-characterized model of repeated dural inflammatory stimulation (IS), in which an inflammatory stimulant is infused over the dura, also results in persistent headache behavior that has been accepted as a valid model for drug testing. Although the pathological mechanisms between the two models are different, one being considered idiopathic or a spontaneous model and the other inflammatory in nature, the precise mechanism(s) remain elusive. The aim of this study is to determine the dose response of the (R)-isomer of isometheptene on trigeminal sensitivity in the STA and IS rat models and study the mechanism of action of isometheptene. Poster presented at: American Headache Society 58th Annual Scientific Meeting in San Diego CA.https://jdc.jefferson.edu/neurosurgeryposters/1005/thumbnail.jp