Cortical spreading depression decreases Fos expression in rat periaqueductal gray matter

Abstract

h i g h l i g h t s• Cortical spreading depression (CSD) likely underlies migraine aura.• Periaqueductal gray matter (PAG) controls pain and autonomic functions.• CSD provocation decreased neuronal Fos in PAG and Edinger-Westphal nucleus of rats.• The numbers of CSDs correlated negatively with Fos-immunoreactive counts. a r t i c l e i n f o a b s t r a c tThe migraine headache involves activation and central sensitization of the trigeminovascular pain pathway. The migraine aura is likely due to cortical spreading depression (CSD), a propagating wave of brief neuronal depolarization followed by prolonged inhibition. The precise link between CSD and headache remains controversial. Our objectives were to study the effect of CSD on neuronal activation in the periaqueductal grey matter (PAG), an area known to control pain and autonomic functions, and to be involved in migraine pathogenesis. Fos-immunoreactive nuclei were counted in rostral PAG and Edinger-Westphal nuclei (PAG-EWn bregma −6.5 mm), and caudal PAG (bregma −8 mm) of 17 adult male Sprague-Dawley rats after KCl-induced CSD under chloral hydrate anesthesia. Being part of a pharmacological study, six animals had received, for the preceding 4 weeks daily, intraperitoneal injections of lamotrigine (15 mg/kg), six others had been treated with saline, while five sham-operated animals served as controls. We found that the number of Fos-immunoreactive nuclei in the PAG decreased after CSD provocation. There was no difference between lamotrigine-and saline-treated animals. The number of CSDs correlated negatively with Fos-immunoreactive counts. CSD-linked inhibition of neuronal activity in the PAG might play a role in central sensitization during migraine attacks and contribute to a better understanding of the link between the aura and the headache.

Optogenetic Spreading Depression Elicits Trigeminal Pain and Anxiety Behavior

“…Unilateral SD can induce bilateral activation of brain regions relevant for pain. For example, unilateral SD increased c‐fos expression bilaterally in periaqueductal gray 45 and paraventricular hypothalamus 46 . Indeed, migraine‐associated cutaneous allodynia develops in a stepwise fashion with progressive sensitization of higher order (eg, bilateral) neuronal populations 47 .…”

Lamotrigine in the Prevention of Migraine With Aura: A Narrative Review

“…LTG was initially approved for treatment of generalized and partial seizures . At clinically relevant doses, LTG strongly reduces brain hyperexcitability and CSD in various experimental models . The drug inhibits several voltage‐gated sodium channels in the CNS through a voltage‐ and frequency‐dependent blockade.…”