The nonpeptide calcitonin gene-related peptide receptor antagonist BIBN4096BS lowers the activity of neurons with meningeal input in the rat spinal trigeminal nucleus.
Calcitonin gene-related peptide (CGRP) has been suggested to play a major role in the pathogenesis of migraines and other primary headaches. CGRP may be involved in the control of neuronal activity in the spinal trigeminal nucleus (STN), which integrates nociceptive afferent inputs from trigeminal tissues, including intracranial afferents. The activity of STN neurons is thought to reflect the activity of central trigeminal nociceptive pathways causing facial pain and headaches in humans. In a rat model of meningeal nociception, single neuronal activity in the STN was recorded. All units had receptive fields located in the exposed parietal dura mater. Heat and cold stimuli were repetitively applied to the dura in a fixed pattern of ramps and steps. The nonpeptide CGRP receptor antagonist BIBN4096BS was topically applied onto the exposed dura or infused intravenously. BIBN4096BS (300 microg/kg, i.v.) reduced spontaneous activity by approximately 30%, the additional dose of 900 microg/kg intravenously by approximately 50% of the initial activity, whereas saline had no effect. The activity evoked by heat ramps was also reduced after BIBN4096BS (900 microg/kg, i.v.) by approximately 50%. Topical administration of BIBN4096BS (1 mm) did not significantly change the spontaneous neuronal activity within 15 min. We conclude that the endogenous release of CGRP significantly contributes to the maintenance of spontaneous activity in STN neurons. Blockade of CGRP receptors, possibly at central and peripheral sites, may therefore be an effective way to decrease nociceptive transmission. This may offer a new therapeutic strategy for the treatment of facial pain and primary headaches.
Institute of Physiology and Experimental Pathophysiology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany.
Michael Jochen Marco
MJ
Fischer
Stanislav
S
Koulchitsky
Karl
K
Messlinger
D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000031:analogs & derivatives; D004388:Dura Mater / Q000502:physiology; D004558:Electric Stimulation; D004594:Electrophysiology; D008297:Male; D008578:Meninges / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013238:Stereotaxic Techniques; D014279:Trigeminal Nucleus, Spinal / Q000187:drug effects / Q000502:physiology*
D010879:Piperazines; D011799:Quinazolines; D015740:Calcitonin Gene-Related Peptide; C406305:olcegepant