title: Modulation of nociceptive dural input to the trigeminocervical complex through GluK1 kainate receptors.
abstract: Migraine is a common and disabling neurologic disorder, with important psychiatric comorbidities. Its pathophysiology involves activation of neurons in the trigeminocervical complex (TCC). Kainate receptors carrying the glutamate receptor subunit 5 (GluK1) are present in key brain areas involved in migraine pathophysiology. To study the influence of kainate receptors on trigeminovascular neurotransmission, we determined the presence of GluK1 receptors within the trigeminal ganglion and TCC with immunohistochemistry. We performed in vivo electrophysiologic recordings from TCC neurons and investigated whether local or systemic application of GluK1 receptor antagonists modulated trigeminovascular transmission. Microiontophoretic application of a selective GluK1 receptor antagonist, but not of a nonspecific ionotropic glutamate receptor antagonist, markedly attenuated cell firing in a subpopulation of neurons activated in response to dural stimulation, consistent with selective inhibition of postsynaptic GluK1 receptor-evoked firing seen in all recorded neurons. In contrast, trigeminovascular activation was significantly facilitated in a different neuronal population. The clinically active kainate receptor antagonist LY466195 attenuated trigeminovascular activation in all neurons. In addition, LY466195 demonstrated an N-methyl-d-aspartate receptor-mediated effect. This study demonstrates a differential role of GluK1 receptors in the TCC, antagonism of which can inhibit trigeminovascular activation through postsynaptic mechanisms. Furthermore, the data suggest a novel, possibly presynaptic, modulatory role of trigeminocervical kainate receptors in vivo. Differential activation of kainate receptors suggests unique roles for this receptor in pro- and antinociceptive mechanisms in migraine pathophysiology.
authors: Headache Group, Department of Neurology, University of California, San Francisco, CA, USA Headache Research-Section of Anaesthetics, Pain Medicine and Intensive Care Section, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK, Headache Group, Basic and Clinical Neurosciences, King's College London, London, United Kingdom.
authors: Anna P
authors: AP
authors: Andreou
authors: Philip R
authors: PR
authors: Holland
authors: Michele P
authors: MP
authors: Lasalandra
authors: Peter J
authors: PJ
authors: Goadsby
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000344:Afferent Pathways / Q000502:physiology; D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007478:Iontophoresis; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008576:Meningeal Arteries / Q000294:innervation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000378:metabolism*; D013941:Thymine / Q000031:analogs & derivatives / Q000494:pharmacology; D014278:Trigeminal Nuclei / Q000166:cytology / Q000378:metabolism*
chemical_list: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000409:Alanine; D015740:Calcitonin Gene-Related Peptide; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D018092:Kainic Acid Receptors; D013941:Thymine; C509618:1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl)pyrimidine-2,4-dione; C512994:6-((2-carboxy-4,4-difluoro-1-pyrrolidinyl)methyl)decahydro-3-isoquinolinecarboxylic acid