Modulation of nocioceptive transmission with calcitonin gene-related peptide receptor antagonists in the thalamus.

Calcitonin gene-related peptide receptor antagonists are effective acute migraine treatments without the vascular contraindications associated with triptans. While it has been demonstrated that calcitonin gene-related peptide receptor antagonists act in the central nervous system, their effects in preclinical migraine models have been investigated in only the trigeminocervical complex. Migraine is a complex neurological disorder; sites in the brainstem and forebrain are clearly involved in its expression. We have performed electrophysiological recordings in thalamic neurons of rats responding to nocioceptive trigeminovascular inputs and tested the effect of olcegepant, a calcitonin gene-related peptide receptor antagonist (1 mg/kg, intravenously), on cell firing. We further tested the effect of microiontophoresed calcitonin gene-related peptide and the receptor antagonists calcitonin gene-related peptide 8-37 and olcegepant on thalamic cell firing, elicited by stimulation of the superior sagittal sinus or by microiontophoretic application of l-glutamate. Additionally, we used immunofluorescent staining to demonstrate the presence of functional calcitonin gene-related peptide receptors in the ventroposteromedial thalamic nucleus by specifically co-staining for the calcitonin gene-related peptide receptor subunits calcitonin receptor-like receptor and receptor activity modifying protein 1. Intravenously administered olcegepant significantly inhibited cell firing evoked by stimulation of the superior sagittal sinus as well as the background activity. Microiontophoresis of calcitonin gene-related peptide 8-37 also showed a significant inhibition of l-glutamate-evoked cell firing and firing evoked by stimulation of the superior sagittal sinus. Immunofluorescent staining confirmed the presence of the components of a functional calcitonin gene-related peptide receptor, the calcitonin receptor-like receptor and the receptor activity modifying protein 1, within the area of the ventroposteromedial thalamic nucleus. This is the first report on the efficacy of calcitonin gene-related peptide receptor antagonists at the level of third-order neurons in the migraine pathway, showing that the central effects of calcitonin gene-related peptide receptor antagonists extend beyond the trigeminocervical complex at least to the sensory thalamus.

[1]  G. A. Lambert,et al.  Stimulation of cranial vessels excites nociceptive neurones in several thalamic nuclei of the cat , 2006, Experimental Brain Research.

[2]  J. Mcculloch,et al.  Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: Trigeminal origin and co-existence with substance P , 1985, Neuroscience Letters.

[3]  G. Lenzi,et al.  Vascular Dementia: A Cognitive SPET-CBF Activation Study , 2001, Cerebrovascular Diseases.

[4]  Trevor W. Stone,et al.  Microiontophoresis and pressure ejection , 1985 .

[5]  P. Goadsby,et al.  Serotonin receptors modulate trigeminovascular responses in ventroposteromedial nucleus of thalamus: A migraine target? , 2006, Neurobiology of Disease.

[6]  F. Bloom.  To spritz or not to spritz: the doubtful value of aimless iontophoresis. , 1974, Life sciences.

[7]  D. Jacobowitz,et al.  Autoradiographic distribution of 125I calcitonin gene-related peptide binding sites in the rat central nervous system , 1985, Peptides.

[8]  S. Enna,et al.  The parafasciculus thalami as a site for mediating the antinociceptive response to GABAergic drugs , 1986, Brain Research.

[9]  P. Goadsby,et al.  Vasoactive peptide release in the extracerebral circulation of humans during migraine headache , 1990, Annals of neurology.

[10]  S. Feldman,et al.  Alterations produced by cortisol in the spontaneous activity and responsiveness to sensory stimuli of single cells in the tuberal hypothalamus of the rat. , 1973, Neuroendocrinology.

[11]  R. Heavens,et al.  Cloning, characterization and central nervous system distribution of receptor activity modifying proteins in the rat , 2001, The European journal of neuroscience.

[12]  P. Goadsby,et al.  GABA and valproate modulate trigeminovascular nociceptive transmission in the thalamus , 2010, Neurobiology of Disease.

[13]  H. Wolff,et al.  EXPERIMENTAL STUDIES ON HEADACHE , 1942 .

[14]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[15]  C. Winborn,et al.  Sensitization of Calcitonin Gene-Related Peptide Receptors by Receptor Activity-Modifying Protein-1 in the Trigeminal Ganglion , 2007, The Journal of Neuroscience.

[16]  Kenji Sakuma,et al.  Somatosensory evoked high-frequency oscillations in migraine patients , 2004, Clinical Neurophysiology.

[17]  Ferrari,et al.  Drug therapy: Migraine - Current understanding and treatment. , 2002 .

[18]  P. Armitage,et al.  Statistical methods in medical research. , 1972 .

[19]  K. Messlinger,et al.  Calcitonin gene-related peptide receptor antagonist olcegepant acts in the spinal trigeminal nucleus. , 2009, Brain : a journal of neurology.

[20]  P. Goadsby,et al.  Calcitonin gene‐related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat , 2004, British journal of pharmacology.

[21]  R. Lipton,et al.  Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials , 2001, The Lancet.

[22]  R. Lipton,et al.  Migraine--current understanding and treatment. , 2002, The New England journal of medicine.

[23]  Peter J. Goadsby,et al.  A Report on the Journal 2004 , 2004 .

[24]  C. Lines,et al.  Randomized, controlled trial of telcagepant for the acute treatment of migraine , 2009, Neurology.

[25]  M. Wigglesworth,et al.  Non-peptidic antagonists of the CGRP receptor, BIBN4096BS and MK-0974, interact with the calcitonin receptor-like receptor via methionine-42 and RAMP1 via tryptophan-74 , 2010, Biochemical and biophysical research communications.

[26]  J. Winn,et al.  Brain , 1878, The Lancet.

[27]  K. Rudolf,et al.  Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist , 2000, British journal of pharmacology.

[28]  D. van der Kooy,et al.  Enrichment of a vasoactive neuropeptide (calcitonin gene related peptide) in the trigeminal sensory projection to the intracranial arteries , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[29]  J. Longmore,et al.  Effects of two truncated forms of human calcitonin-gene related peptide: implications for receptor classification. , 1994, European journal of pharmacology.

[30]  G. A. Lambert,et al.  Craniovascular application of capsaicin activates nociceptive thalamic neurones in the cat , 1991, Neuroscience Letters.

[31]  R. Lipton,et al.  Prevalence and Burden of Migraine in the United States: Data From the American Migraine Study II , 2001, Headache.

[32]  P. Goadsby,et al.  Nitric oxide synthase inhibitors can antagonize neurogenic and calcitonin gene‐related peptide induced dilation of dural meningeal vessels , 2002, British journal of pharmacology.

[33]  J. Longmore,et al.  Receptor Activity-modifying Protein 1 Determines the Species Selectivity of Non-peptide CGRP Receptor Antagonists* 210 , 2002, The Journal of Biological Chemistry.

[34]  J F Toole,et al.  The global burden of disease study: implications for neurology. , 2000, Archives of neurology.

[35]  David W Dodick,et al.  Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial , 2008, The Lancet.

[36]  P. Goadsby,et al.  Propranolol modulates trigeminovascular responses in thalamic ventroposteromedial nucleus: a role in migraine? , 2004, Brain : a journal of neurology.

[37]  Karl J. Friston,et al.  A positron emission tomographic study in spontaneous migraine. , 2005, Archives of neurology.

[38]  R. Hargreaves,et al.  Intravital Microscope Studies on the Effects of Neurokinin Agonists and Calcitonin Gene-Related Peptide on Dural Vessel Diameter in the Anaesthetized Rat , 1997, Cephalalgia : an international journal of headache.

[39]  Richard S. J. Frackowiak,et al.  A PET study in spontaneous migraine , 2004 .

[40]  Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials. , 1996, Endocrine reviews.

[41]  S. Wimalawansa,et al.  Comparative study of distribution and biochemical characterization of brain calcitonin gene-related peptide receptors in five different species , 1993, Neuroscience.

[42]  J. Olesen.  The International Classification of Headache Disorders , 2008, Headache.

[43]  D. Yarnitsky,et al.  The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. , 2000, Brain : a journal of neurology.

[44]  H. Wolff,et al.  EXPERIMENTAL STUDIES ON HEADACHE: PAIN-SENSITIVE STRUCTURES OF THE HEAD AND THEIR SIGNIFICANCE IN HEADACHE , 1940 .

[45]  K. Messlinger,et al.  The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus , 2005, The Journal of Neuroscience.

[46]  L. Costa,et al.  A comparison of the antinociceptive responses to the GABA-receptor agonists THIP and baclofen , 1985, Neuropharmacology.

[47]  Y. Kubota,et al.  Autoradiographic localization of calcitonin gene-related peptide binding sites in human and rat brains , 1986, Brain Research.

[48]  P. Goadsby,et al.  The trigeminovascular system and migraine: Studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats , 1993, Annals of neurology.

[49]  J. Olesen,et al.  Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. , 2004, The New England journal of medicine.