Michael L. Oshinsky - US grants

[unreadable] DESCRIPTION (provided by applicant): Headache is the most common pain-related complaint and the seventh leading ailment seen in medical practice, accounting for 18 million physician visits each year 1. Recent evidence from a variety of sources indicates that inflammation of the dura is important for recurrent headache disorders. Chronic daily headache (CDH) is a pain disorder characterized by >15 headache days per month and affects up to 4% of the general population. Most cases of CDH evolve from episodic migraine. Little is known about how episodic migraine transforms into CDH, in part, because there are currently are no validated animal models to study the pathophysiology of CDH. In the preliminary data for this application, we report the development of a model of CDH using repeated application of inflammatory soup to the dura in awake, behaving rats. These data indicate that repetitive stimulation of the dura with an inflammatory soup (IS) leads to chronic pressure and brush allodynia in the periorbital region of the rat. Following the first few infusions of IS, changes in sensory thresholds resolve in hours. After multiple infusions, there is a chronic allodynic state that persists. In addition, in many of the rats, allodynia spreads to extracephalic regions of the body. Based on our preliminary findings, we propose the following 2 specific aims to test the hypothesis that repetitive infusion of IS on the dura is an accurate model for studying the pathophysiology of chronic daily headache. These aims will demonstrate that this system models CDH because it responds to proven clinical treatments of CDH in humans. Aim 1 will test the hypothesis that established preventive treatments for migraine in humans will block the transition of the rats from episodic to chronic trigeminal pain following repetitive IS infusion on the dura. Aim 2 will test the hypothesis that acute migraine treatments such as triptans are less effective in rats that have received chronic IS infusions. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] Chronic daily headache (CDH) is a neurological disorder characterized by >15 headache days per month and affects up to 4% of the general population. Most cases of CDH evolve from episodic headache. CDH patients often report chronic pericranial tenderness (allodynia) with episodes of increased headache pain. Both a long history of headache and a high frequency of headache attacks are risk factors for the progression of episodic to chronic headache. Little is known about the physiological mechanism for the transition from episodic headache to CDH. One theory is that the pain phase of migraine involves nociceptor activation on the dura due to neurogenic inflammation. According to this theory, recurrent headache patients experience repeated attacks of inflammation and nociceptor activation on the dura over time. The overall aim of this study is to assess the mechanism of the progression of episodic to chronic headache following repeated dural inflammation. Studies show that repeated nociceptor activation produces long-lasting changes in the peripheral trigeminal neurons and their central projections in the brain. This can increase the perception of pain in secondary or referred areas due to activity-dependent neuronal plasticity. We have developed a model of recurrent headache in rat where we can induce inflammatory stimulation on the dura at fixed intervals over weeks. Repeated, episodic infusion of inflammatory soup (IS) on the dura of rats models the episodic activation of the dura in patients with recurrent headache. We propose to investigate the electrophysiological and neurochemical factors important for the progression of episodic to chronic trigeminal pain using this model. We hypothesize that repeated inflammatory stimulation of the dura induces chronic long lasting changes in trigeminal sensory processing in our rat model of CDH. In order to test this hypothesis, we propose 3 specific aims. Aim 1 will test the hypothesis that there is a critical frequency of inflammatory stimulation of the dura that causes the transition to low trigeminal thresholds. Aim 2 will test the hypothesis that the transition to chronically low trigeminal thresholds induces a long lasting hyperresponsive state of the electrophysiological and neurochemical responses in the trigeminal nucleus caudalis. Aim 3 will test the hypothesis that clinical headache treatment strategies, that effectively block allodynia and sensitization in patients, with block the transition of rats from episodic to chronic trigeminal pain following recurrent inflammatory stimulation of the dura. Project Narrative Recurrent headache is the most common pain-related complaint and the seventh leading ailment seen in medical practice, accounting for 18 million physician visits each year. Chronic daily headache is a disorder that affects up to 4% of the general population. The overall aim of this study is to assess the mechanism of the progression of episodic to chronic headache following repeated dural inflammation. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): A healthy moist ocular surface is essential for proper visual functioning. It requires cooperation of an integrated system called the Lacrimal Functional Unit, which consists of the ocular surface tissues, secretory glands, and the nervous system, that together produce and maintain a normal tear film. A disturbance in any group of these components leads to dry eye. The corneal sensory afferents are one of these components. Their activation is considered to be critical to basal tear production, and thus their dysfunction could cause a chronic lack of tears, resulting in dry eye. However, despite a great amount of work done to characterize the corneal afferents, their roles in the lacrimation reflex or dry eye disease still remain to be determined. Recently, we identified a special type of cold-sensitive corneal nerve that is activated by a variety of ocular stimulations thought to be critical for tear production: drying of the cornea, gentle cooling, tear evaporation, and hyperosmolar tears. Evidence indicates that dry eye disease is in part a dysfunction of the mechanisms that detect ocular surface conditions such as cooling of the cornea and the hyperosmolar tears. Thus, we hypothesize that activation of this special type of corneal afferent will induce tear production and their dysfunction contributes to dry eye disease. If so, a selective destruction of these cold-sensitive corneal afferents should lead to dry eye. Recent evidence indicates that members of the nerve membrane receptors (TRPM8, TRPV1, TRPA1) reside in this special type of corneal afferent involved in tear production;that TRPM8 receptors mediate the cooling response;and TRPV1/TRPA1 receptors mediate the hyperosmolar response. We hypothesize that activation of these receptors together constitutes the responses of these cold-sensitive corneal afferents to drying of the cornea and leads to tearing. Thus, genetically engineered mutant mice specifically lacking these receptors should produce very few tears and exhibit dry eye. We will also show that these mutant mice display other signs of dry eye diseases such as inflammation of the ocular surface, which would damage the integrity of the ocular surface tissues, producing the abnormal morphology of the corneal and the conjunctival epithelia. Finally, we will demonstrate immunohistochemically that some well-known models of dry eye disease lack these receptors, implying that this fact is one reason that they have dry eye. If the aims of these studies are achieved, the proposed research will lead to a better understanding of the cellular and molecular mechanisms underlying the activation of the lacrimation reflex and dry eye disease, and may provide new targets for pharmacological treatments for dry eye diseases. PUBLIC HEALTH RELEVANCE: Dry eye disease afflicts millions of Americans annually and is the most frequent complaint from patients visiting eye care clinics. It also could lead to serious visual disturbances including blindness. We propose to study the corneal afferent mechanisms underlying the tear production reflex and to attempt to establish its relationship to dry eye disease. The results from this study may lead to a new approach to treatments for dry eye disease.