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Even though the set of headaches known as migraine have been difficult to treat with either pharmacotherapy or other approaches, significant progress, particularly in acute episodes, has been made in recent decades. Regardless, much remains to be known about the genesis of migraine headaches, and their treatment, especially in the chronic, prophylactic sense. In this chapter, migraine is introduced in the context of various biochemical factors that have not been traditionally associated with headache. These include neural elements such as astrocytes and chemical parameters associated with metabolic, affective and sleep regulation. The primary focus is to suggest signaling pathways that might be tested for playing a role in the headaches and which could become targets for new drug development. Adipokines like leptin are noteworthy in this regard.

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