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Keywords:

  • cerebrospinal fluid;
  • Na+;
  • K+ -ATPase transporter (NKAT);
  • capillary endothelial cell (CEC)

(Headache 2010;50:459-478)

Background.— Cerebrospinal fluid sodium concentration ([Na+]csf) increases during migraine, but the cause of the increase is not known.

Objective.— Analyze biochemical pathways that influence [Na+]csf to identify mechanisms that are consistent with migraine.

Method.— We reviewed sodium physiology and biochemistry publications for links to migraine and pain.

Results.— Increased capillary endothelial cell (CEC) Na+, K+, -ATPase transporter (NKAT) activity is probably the primary cause of increased [Na+]csf. Physiological fluctuations of all NKAT regulators in blood, many known to be involved in migraine, are monitored by receptors on the luminal wall of brain CECs; signals are then transduced to their abluminal NKATs that alter brain extracellular sodium ([Na+]e) and potassium ([K+]e).

Conclusions.— We propose a theoretical mechanism for aura and migraine when NKAT activity shifts outside normal limits: (1) CEC NKAT activity below a lower limit increases [K+]e, facilitates cortical spreading depression, and causes aura; (2) CEC NKAT activity above an upper limit elevates [Na+]e, increases neuronal excitability, and causes migraine; (3) migraine-without-aura may arise from CEC NKAT over-activity without requiring a prior decrease in activity and its consequent spreading depression; (4) migraine triggers disturb, and treatments improve, CEC NKAT homeostasis; (5) CEC NKAT-induced regulation of neural and vasomotor excitability coordinates vascular and neuronal activities, and includes occasional pathology from CEC NKAT-induced apoptosis or cerebral infarction.