The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

Abstract

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 g/kg, i.v.) reduced spontaneous activity by ϳ30%, the additional dose of 900 g/kg intravenously by ϳ50% of the initial activity, whereas saline had no effect. The activity evoked by heat ramps was also reduced after BIBN4096BS (900 g/kg, i.v.) by ϳ50%. 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.

Activation of TRPV1 Mediates Calcitonin Gene-Related Peptide Release, Which Excites Trigeminal Sensory Neurons and Is Attenuated by a Retargeted Botulinum Toxin with Anti-Nociceptive Potential

“…The excitatory effect of CGRP appears to be mediated via activation of CGRP1 receptors (Poyner, 1995) because it was prevented by CGRP8 -37. These findings along with previous in vivo studies, showing its significant blockade of spontaneous spiking activity of sensory neurons in the trigeminal complex (Fischer et al, 2005), indicate that there is adequate scope for elevated release of this peptide to induce central nociceptive sensitization.…”

CGRP Receptor Antagonism and Migraine

“…87 If, however, the olcegepant is given by local microiontophoresis (to circumvent the bloodbrain barrier), it is a potent inhibitor of activated trigeminocervical neurons in vivo, 100 or if given systemically in very high doses. 101 These studies demonstrate the presence of functional CGRP receptors on the second-order trigeminal neurons.…”

Sensitization of Calcitonin Gene-Related Peptide Receptors by Receptor Activity-Modifying Protein-1 in the Trigeminal Ganglion

“…Indeed, the pertinent sites of CGRP and BIBN4096BS actions during migraine remain to be established (Durham, 2004;Strassman and Levy, 2006). Based on recent evidence, peripheral CGRP receptors at the dura alone are not sufficient to activate trigeminal ganglion nociceptors (Fischer et al, 2005;Levy et al, 2005). Although this does not preclude a peripheral autoreceptor role, it does emphasize the potential importance of autoreceptors on ganglion cell bodies and/or central projections in the trigeminocervical complex of the brainstem.…”

“…Second, CGRP receptors are present on dural mast cells, from which CGRP can release cytokines and inflammatory agents during neurogenic inflam-mation (Theoharides et al, 2005). Third, there are postsynaptic CGRP receptors on second-order sensory neurons within brainstem trigeminal nuclei that can also be inhibited by BIBN4096BS (Storer et al, 2004;Fischer et al, 2005;Levy et al, 2005).…”