Scavenging CGRP is another approach to migraine treatment. This requires large molecules with good tolerability, and some biologically occurring molecular classes seem to be well suited in this respect. One group is certainly antibodies, which are widely used therapeutically [
21,
22]. Anti-CGRP antibodies, eptinezumab (ALD403 by Alder Biopharmaceuticals) galcanezumab (LY2951742 by Eli Lilly) and fremanezumab (TEV-48125 by Teva Pharmaceuticals), have a half-life of 21–48 days. The completed phase II trials for the prevention of migraine attacks in patients suffering from frequent migraine attacks showed promising results and the phase III trials are ongoing [
23‐
26].
Another less explored option is chirally inverse
l-oligonucleotides (
l-aptamers, also known as Spiegelmers). RNA aptamers in the naturally occurring
d-configuration that are enzymatically degraded by nucleases. In contrast,
l-aptamers are stable in blood, resulting in a long half-life [
27]. Such mirror-image (
l-)aptamers have been developed to target gonadotropin releasing hormone, enterotoxin B, vasopressin, substance P, nociceptin, CCL2/MCP-1, amylin, ghrelin, hepcidin, CXCL12/SDF-1, C5a, sphingosine 1-phosphate and glucagon [
27]. Three
l-aptamers have passed clinical phase I and IIa trials. NOX-H94 for hepcidin completed a phase I trial (van Eijk et al. 2014), and NOX-E36 for CCL2 as well as NOX-A12 against CXCL12/SDF-1 have completed and published Phase IIa trials [
28,
29]. Beyond stability, the rate of excretion is important for the plasma half-life. The latter can be prolonged by covalent coupling of polyethylene glycol moieties to these substances [
30]. NOX-C89, a PEGylated variant of the first CGRP-binding
l-aptamer, STAR-F12-Δ43–48 [
31], that preferentially binds to mouse/rat αCGRP has been used to elucidate strain differences in rats regarding CGRP release and behavioral responses to noxious heat [
32]. It was furthermore reported to reduce CGRP-dependent vasodilatation and blood flow in the exposed rat dura mater [
33‐
35]. A newer anti-αCGRP
l-aptamer NOX-L41, with equal affinity to mouse/rat αCGRP and an even higher affinity to human αCGRP, was shown to inhibit neurogenic plasma protein extravasation [
36]. Before clinical validation, new strategies are tested in preclinical models [
34,
37]. We chose to investigate neuronal firing in the trigeminal pathway in rats following our prior study, in which we examined the effect of the CGRP receptor antagonist olcegepant. Neuronal activity in the trigeminal system, particularly in the neurons receiving input from the cranial dura mater, is assumed to reflect headache. Therefore, the effects of an anti-CGRP
l-aptamer on neuronal activity in the spinal trigeminal nucleus were tested. This approach has limited output at relatively high effort, but can directly asses the activity considered to underlie headaches. To this end experiments on cats and rats are established. Results do not point to a higher predictive value for human disease for one of these species; the current study used rats as in our prior work investigating olcegepant. The purpose of this study was to investigate the effect of anti-αCGRP
l-RNA oligomers on the spontaneous and heat-evoked firing of spinal trigeminal neurons as a model of meningeal nociception.