Amplitudes and propagation of cortical spreading depolarization (CSD) in adult rats are influenced by Calcitonin gene-related peptide (CGRP).

It is known from the literature that CGRP plays an important role in migraine and antagonizing CGRP is an effective preventing treatment against migraine pain. CGRP is able to increase neuronal excitability. Further it has been shown that a CSD - that is known to be the correlate of the migraine aura - can release CGRP in rat neocortical slices. Whether CGRP enhances brain’s susceptibility for CSD or influence CSD itself in vivo has not been investigated yet. To test this, we applied CGRP at different concentrations topically to a restricted part of the cortical surface and compared the electrocorticogram, regional cerebral blood flow (rCBF) and parameters of CSD in the treated region with the untreated brain area.

In spontaneously breathing anesthetized adult rats (sodium thiopentone, 100 mg/kg, i.p.) CSDs were recorded in cerebral cortex with two pairs of glass micropipettes (distance 5-6 mm) at depths of 400 and 1200 µm in two areas of the cortex, separated by a wall. In addition, in the treated area CSD-related changes in extracellular potassium concentration ([K+]e) were measured with a micropipette filled with Corning IE-190 ionic exchanger. In the untreated area, CSD was elicited by a microinjection of 1 M KCl (100 kPa, 300 ms up to 1 s, depth 1200 µm) into the grey matter at intervals of 30 min. In the remote area 100 µl of CGRP at concentrations from 10-8 M to 10-5 M (only one concentration per experiment) were applied topically and left there for three hours. In both cortical areas rCBF was measured.

In all rats tested, a pulse of KCl elicited a single propagating CSD. The topical application of CGRP to the brain surface reduced the amplitudes of CSD in the treated area (10-5 M to 60 % of controls; 10-8 M to 70 % of controls; untreated to 85-90 % of controls) and slowed the propagation velocity (10-5 M from 3.0 to 2.6 cm/s; 10-8 M from 2.4 to 2.2 cm/s). Rarely spontaneous CSD were observed originating from the CGRP-treated area. In another few rats, CGRP induced focal ictal activity after 2-3 hours of application that did not spread into the untreated cortex. Focal ictal activity occurred at intervals of 8-10 min and was accompanied by transient increases in [K+]e. However, so far neither the ignition of CSDs nor the induction of focal ictal activity showed a dose-dependency to CGRP.

Our results identify the neuropeptide CGRP as a candidate that could interfere with CSD by changing neuronal excitability.