Abstract
BackgroundCalcitonin gene-related peptide (CGRP) plays a major role in the pathogenesis of migraine and other primary headaches. Spinal trigeminal neurons integrate nociceptive afferent input from trigeminal tissues including intracranial afferents, and their activity is thought to reflect facial pain and headache in man. CGRP receptor inhibitors and anti-CGRP antibodies have been demonstrated to be therapeutically effective in migraine. In parallel, CGRP receptor inhibition has been shown to lower spinal trigeminal neuron activity in animal models of meningeal nociception.MethodsIn a rat model of meningeal nociception, single cell activity of neurons in the spinal trigeminal nucleus with meningeal afferent input was recorded to test a further pharmacological approach, scavenging CGRP with a CGRP-binding l-RNA oligonucleotide, the l-aptamer NOX-C89. Cumulative ascending doses of NOX-C89 were intravenously infused.ResultsSpontaneous activity of spinal trigeminal neurons did not change after 0.05 mg/kg NOX-C89, however, after additional infusion of 0.5 mg/kg and 5 mg/kg NOX-C89, spontaneous activity was dose-dependently reduced. Identical doses of a control l-aptamer had no effect. This pharmacological effect of NOX-C89 was observed 10–25 min after infusion, but no difference was detected in the period 0–5 min. For comparison, the previously investigated CGRP receptor antagonist olcegepant had reduced activity within 5 min after infusion. Alongside the reduced spontaneous activity, after infusion of NOX-C89 the heat-induced neuronal activity was abolished.ConclusionsScavenging CGRP by mirror-image RNA aptamers provides further evidence that this approach can be used to control spinal trigeminal activity.
Highlights
Calcitonin gene-related peptide (CGRP) plays a major role in the pathogenesis of migraine and other primary headaches
The neuropeptide calcitonin gene-related peptide (CGRP), found in a subset of polymodal nociceptive afferents innervating intracranial tissues, is considered an important endogenous mediator in the generation of headaches. This notion is based on the observation that infusion of CGRP in migraineurs can trigger a migraine attack [1, 2] and, more importantly, inhibition of the CGRP system has been proven beneficial in migraine patients, whereby different ways of interfering with the CGRP system appear to be effective: Inhibition of CGRP release by triptans, CGRP
CGRP does not excite or sensitize meningeal nociceptors [14], but there are several lines of evidence suggesting a central site of action of CGRP, including the observation that CGRP receptor inhibition microiontophoretically injected at the recording site can reduce spinal trigeminal activity [15]
Summary
Calcitonin gene-related peptide (CGRP) plays a major role in the pathogenesis of migraine and other primary headaches. The neuropeptide calcitonin gene-related peptide (CGRP), found in a subset of polymodal nociceptive afferents innervating intracranial tissues, is considered an important endogenous mediator in the generation of headaches. This notion is based on the observation that infusion of CGRP in migraineurs can trigger a migraine attack [1, 2] and, more importantly, inhibition of the CGRP system has been proven beneficial in migraine patients, whereby different ways of interfering with the CGRP system appear to be effective: Inhibition of CGRP release by triptans, CGRP. The receptor occupancy of an effective antimigraine dose of telcagepant was lower than what is expected to be necessary [19], but useful levels of inhibition are rather based on general observations than any specific findings in headaches, and further depend on e.g. target desensitization, regional target composition or endogenous ligands [20]
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