Migraine Pathophysiology:Thalamus and Extended Allodynia

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DESCRIPTION (provided by applicant): Migraine is a unilateral throbbing headache commonly associated with restricted allodynia (affecting the referred pain area) as well as extended allodynia (affecting other parts of the head and body). Our electrophysiological studies have shown that sensitized meningeal nociceptors can mediate the throbbing and that sensitized trigeminovascular neurons in the medullary dorsal horn can mediate cephalic allodynia on the migraine side of the face, but'not elsewhere. The objectives of this grant proposal are to gain novel insights into the pathophysiology of extended allodynia during migraine by studying neuronal plasticity of nociceptive thalamic neurons that process sensory information from the dura and from cephalic and extracephalic skin. Three working hypotheses will be tested. Hypothesis 1 will test whether ventral posteromedial (VPM) thalamic neurons can mediated the spread of allodynia from one side of the face to the other upon their sensitization. Hypothesis 2 will test whether posterior (PO) thalamic neurons can mediated the spread of allodynia from one side of the face to the limbs and trunk upon their sensitization. Hypothesis 3 will test whether dura-sensitive VPM and PO neurons project to the first somatosensory (SI) cortex and/or the granular insular (GI) cortex. In Specific Aims 1a-c and 2a-c we will map receptive fields, record ongoing activity and determine physiological response properties of VPM and PO neurons before and after local application of 'inflammatory soup' to the dura - a stimulus we used successfully to induce lasting sensitization in peripheral (trigeminal ganglion) and central (dorsal horn) dura-sensitive neurons in our animal model of intracranial pain (such as migraine). In Specific Aims 3a, b we will map cortical projections of dura-sensitive VPM and PO neurons in effort to gain more insight into the different role they may play in localization, laterality, intensity, and affective aspects of migraine headache. After studying the consequences of neuronal sensitization in the trigeminal ganglion and medullary dorsal horn in our animal model of intracranial pain, this grant proposal is a natural 'next step' in our quest to understand better the pathophysiology of migraine. By studying the extended allodynia of migraine - a clinical symptom we characterized with a scientific rigor in patients - this grant proposal opens a unique window into the biological meaning of activity and activation of sensitized thalamic neurons.