• migraine;
  • cluster headache;
  • trigeminal autonomic cephalgias;
  • defense reaction;
  • fight-or-flight reaction;
  • sickness behavior

(Headache 2010;50:273-289)

Objective.— The objective of this study is to present a view of the primary headaches as genetically determined behavioral responses consistent with sickness behavior and defense reaction, respectively.

Background and Design.— A review of the literature bearing on the behavioral, humoral, and functional imaging aspects of the primary headaches shows that migraine and cluster headache (CH) are pain conditions characterized by different behaviors during the attacks. Here it is postulated that the behavioral responses to migraine and CH are evolutionary conserved reactions consistent with sickness behavior and defense reaction.

Results.— The sickness behavior observed during migraine attacks is a pan-mammalian adaptive response to internal and external stressors, characterized by withdrawal and motor quiescence, sympatho-inhibition and lethargy, in which visceral pain signals a homeostatic imbalance of the body and/or brain. In contrast, the defense reaction in CH consists of a fight-or-flight reaction, with motor restlessness and agitation, in which pain is exteroceptive in kind.

Conclusion.— These different behavioral responses are thus specific to different kinds of pain, distinguished by the behavioral significance of the pain (visceral pain in migraine vs exteroceptive pain in CH), and imply brain matrices involving different networks in the brainstem, hypothalamus, and forebrain regions that engender evolutionarily conserved adaptive genetic responses. Cytokines play an important role in their development. Predictions and limitations of the hypothesis are discussed together with implications for genetic studies on headaches.