PT  - JOURNAL ARTICLE
AU  - Jun Zhao
AU  - Dan Levy
TI  - Naproxen inhibits CSD-evoked meningeal afferent mechanosensitization but not prolonged activation: a role for cortical oligemia and hypoxia?
AID  - 10.1101/149278
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 149278
4099  - http://biorxiv.org/content/early/2017/06/12/149278.short
4100  - http://biorxiv.org/content/early/2017/06/12/149278.full
AB  - We have shown previously that cortical spreading depression (CSD), the underlying cause of the migraine aura, also promotes persistent activation and mechanical sensitization of trigeminal meningeal nociceptors - a likely source of the migrainous intracranial headache. CSD involves a prolonged phase of reduced cerebral blood flow (CBF) and reduced tissue oxygen (tpO2). Here we tested the hypothesis the COX-derived prostaglandins, which mediate the post CSD cortical oligemia and tissue hypoxia, also contribute to CSD-evoked meningeal afferent responses. We employed in-vivo extracellular recording from the trigeminal cell body of meningeal afferents to assess changes in their activity and responses to threshold and suprathreshold mechanical stimulation of the meninges. Single unit recordings were conducted in combination with measurements of cerebral blood flow, using laser Doppler flowmetry, and tissue partial pressure of oxygen (tpO2), using a modified Clark-type Polarographic oxygen microelectrode. The role of COX-mediators was tested by infusing naproxen (10 mg/kg), 60 min before the induction of CSD using a pin prick stimulus made in the frontal cortex. Treatment with naproxen significantly inhibited the development of cortical oligemia, as expected, and also blocked the prolonged reduction in cortical tpO2. Naproxen did not affect the propensity of meningeal afferents to become activated by CSD, or the activation characteristics, but significantly blocked the development of mechanical sensitization. Our data suggest that CSD-evoked release of COX-derived mediators play a key role in the mechanisms that link CSD and mechanical sensitization of meningeal afferents either directly, or indirectly by promoting cortical oligemia and hypoxia.