Abstract
The onset of the headache phase in migraine with aura is believed to involve cortical spreading depression (CSD) and the ensuing activation and sensitization of primary afferent neurons that innervate the intracranial meninges. How CSD enhances meningeal afferent responses remains, nevertheless, unclear. We employed extracellular single-unit recording of meningeal afferents activity and monitored changes in cerebral blood flow and tissue partial pressure of oxygen (tpO2) in anesthetized male rats to test whether the prolonged cerebral oligemia and reduced tpO2 that occur in the wake of CSD contribute to meningeal nociception. Inhibition of cortical cyclooxygenase (COX) activity using naproxen suppressed the CSD-induced cortical oligemia and decreased tpO2 but did not block the associated activation of meningeal afferents. Naproxen, however, distinctly inhibited the CSD-induced afferent mechanical sensitization. Counteracting the CSD-evoked persistent oligemia and reduced (tpO2), by preemptively increasing cerebral blood flow using the K(ATP) channel opener levcromakalim, inhibited CSD-evoked meningeal afferent activation but had no effect on the mechanical sensitization response. These results suggest that in the wake of CSD, the prolonged reductions in cerebral blood flow and tpO2 do not contribute directly to the activation and mechanical sensitization of meningeal afferent responses and further point to distinct mechanisms underlying these distinct afferent responses to CSD. Targeting the activation and mechanical sensitization of meningeal afferents by combining COX inhibition and K(ATP) channel activation could provide a novel therapeutic approach to treat migraine headache.
Significance statement CSD-evoked activation and mechanical sensitization of meningeal afferents is considered a key mechanism underlying the onset of the headache phase in migraine with aura. We report that blocking the CSD-evoked prolonged cortical oligemia and reduced cortical tpO2 by COX inhibition is associated with the inhibition of the afferent sensitization but not their activation, while normalization of these CSD-evoked metabolic perturbations by activating K(ATP) channels inhibits afferent activation but not their 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 and 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.
Footnotes
Conflict of Interest: The authors declare no competing financial interests