Naproxen inhibits CSD-evoked meningeal afferent mechanosensitization but not prolonged activation: a role for cortical oligemia and hypoxia?

Abstract

The onset of the headache phase during attacks of migraine with aura, which occur in about 30% of migraineurs, is believed to involve cortical spreading depression (CSD) and the ensuing activation and sensitization of primary afferent neurons that innervate the intracranial meninges, and their related large vessels. The mechanism by which CSD enhances the activity and mechanosensitivity of meningeal afferents remains poorly understood, but may involve cortical metabolic perturbations. We employed extracellular single-unit recording of meningeal afferent activity and monitored changes in cortical blood flow and tissue partial pressure of oxygen (tpO2) in anesthetized male rats to test whether the prolonged cortical hypoperfusion and reduction in tissue oxygenation that occur in the wake of CSD contribute to meningeal nociception. Suppression of CSD-evoked cortical hypoperfusion with the cyclooxygenase inhibitor naproxen blocked the reduction in cortical tpO2, but had no effect on the activation of meningeal afferents. Naproxen, however, distinctly prevented CSD-induced afferent mechanical sensitization. Counteracting the CSD-evoked persistent hypoperfusion and reduced tpO2 by preemptively increasing cortical blood flow using the K(ATP) channel opener levcromakalim did not inhibit the sensitization of meningeal afferents, but prevented their activation. Our data show that the cortical hypoperfusion and reduction in tpO2 that occur in the wake of CSD can be dissociated from the activation and mechanical sensitization of meningeal afferent responses suggesting that the metabolic changes do not contribute directly to these neuronal nociceptive responses.\n\nSignificance statementCSD-evoked activation and mechanical sensitization of meningeal afferents is thought to mediate the headache phase in migraine with aura. We report that blocking the CSD-evoked cortical hypoperfusion and reduced tpO2 by cyclooxygenase inhibition is associated with the inhibition of the afferent sensitization but not their activation. Normalization of these CSD-evoked metabolic perturbations by activating K(ATP) channels is, however, associated with the inhibition of afferent activation but not sensitization. These results question the contribution of cortical metabolic perturbations to the triggering mechanism underlying meningeal nociception and the ensuing headache in migraine with aura, further point to distinct mechanisms underlying the activation and sensitization of meningeal afferents in migraine and highlight the need to target both processes for an effective migraine therapy.