Dissociation between CSD-Evoked Metabolic Perturbations and Meningeal Afferent Activation and Sensitization: Implications for Mechanisms of Migraine Headache Onset

Abstract

The onset of the headache phase during attacks of migraine with aura, which occur in ∼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 used extracellular single-unit recording of meningeal afferent activity and monitored changes in cortical blood flow and tissue partial pressure of oxygen (tpO) 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 tpO, 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 tpO by preemptively increasing cortical blood flow using the ATP-sensitive potassium [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 tpO 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. Cortical spreading depression (CSD)-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 tissue partial pressure of oxygen 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.

Levcromakalim, an Adenosine Triphosphate‐Sensitive Potassium Channel Opener, Dilates Extracerebral but not Cerebral Arteries

“…46 The increased K + in the extracellular space upon K ATP channel activation can potentially diffuse into the leptomeninges and promote meningeal nociceptors activation. 48 Furthermore, K + channels have a substantial role in nociceptive processing, particularly in determining peripheral hyperexcitability (when closed) and neuronal inhibition (when opened). 48 Furthermore, K + channels have a substantial role in nociceptive processing, particularly in determining peripheral hyperexcitability (when closed) and neuronal inhibition (when opened).…”

Spreading depression as a preclinical model of migraine

“…Two patterns of prolonged nociceptor activation—biphasic activation (brief activation around SD induction followed by delayed, persistent activation, primarily in the Aδ population) and persistent activation with delayed onset (in C unit population)—were observed following SD [35]. SD-evoked prolonged activation of meningeal nociceptors might be related to ongoing basal activity or the number of receptive fields, rather than to the inflammatory and ATP chemosensitivity of the neurons; SD-evoked activation and mechanical sensitization of meningeal afferent responses was dissociated from SD-evoked metabolic perturbations [103]. SD was also found to evoke a delayed meningeal afferent mechanosensitization, which might explain nociceptive processes that underlie the worsening of migraine headache in conditions associated with transiently increased intracranial pressure [104].…”

Cortical spreading depression and meningeal nociception

“…These findings, together with the notion that reduced blood flow and tissue oxygenation lead to the sensitization of nociceptors in other tissues ( Hillery et al, 2011 , MacIver and Tanelian, 1992 , Mense and Stahnke, 1983 ), raises the possibility that the mechanisms responsible for driving dural nociceptors in the wake of CSD involve similar vascular and metabolic changes. We recently investigated this notion by recording the activity of dural nociceptors along with changes in cortical blood flow and tissue oxygenation following CSD ( Zhao and Levy, 2018b ). We have shown that cortical hypoperfusion and decreased oxygen availability coincide with the emergence of the prolonged activation and sensitization of dural nociceptors.…”

“…While COX-derived prostanoids may not promote the CSD-evoked prolonged activation of dural nociceptors, we recently demonstrated COX involvement in mediating their mechanical sensitization ( Zhao and Levy, 2018b ). The mechanism by which COX-derived mediators promote the sensitization of dural nociceptors following CSD remains unclear.…”

“…The mechanism by which COX-derived mediators promote the sensitization of dural nociceptors following CSD remains unclear. It is, however, unlikely to involve cortical hypoperfusion and decreased oxygen availability, given that amelioration of these metabolic responses via the opening of cortical ATP-sensitive potassium (KATP) channels does not inhibit the nociceptor sensitization response ( Zhao and Levy, 2018b ). Whether COX-derived mediators released in the wake of CSD act directly on dural nociceptors to promote their mechanical sensitization or mediate this nociceptive effect by modulating meningeal immune cells remains to be examined.…”