Abstract
The discovery that intravenous (IV) infusions of the neuropeptide PACAP-38 (pituitary adenylyl cyclase activating peptide-38) induced delayed migraine-like headaches in a large majority of migraine patients has resulted in considerable excitement in headache research. In addition to suggesting potential therapeutic targets for migraine, the finding provides an opportunity to better understand the pathological events from early events (aura) to the headache itself. Although PACAP-38 and the closely related peptide VIP (vasoactive intestinal peptide) are well-known as vasoactive molecules, the dilation of cranial blood vessels per se is no longer felt to underlie migraine headaches. Thus, more recent research has focused on other possible PACAP-mediated mechanisms, and has raised some important questions. For example, (1) are endogenous sources of PACAP (or VIP) involved in the triggering and/or propagation of migraine headaches?; (2) which receptor subtypes are involved in migraine pathophysiology?; (3) can we identify specific anatomical circuit(s) where PACAP signaling is involved in the features of migraine? The purpose of this review is to discuss the possibility, and supportive evidence, that PACAP acts to induce migraine-like symptoms not only by directly modulating nociceptive neural circuits, but also by indirectly regulating the production of inflammatory mediators. We focus here primarily on postulated extra-dural sites because potential mechanisms of PACAP action in the dura are discussed in detail elsewhere (see X, this edition).
Highlights
IntroductionThe discovery that intravenous (IV) infusions of the neuropeptide pituitary adenylate cyclase-activating peptide (PACAP)-38 (pituitary adenylyl cyclase activating peptide-38) induced delayed migraine-like headaches in a large majority of migraine patients has resulted in considerable excitement in headache research
The discovery that intravenous (IV) infusions of the neuropeptide pituitary adenylate cyclase-activating peptide (PACAP)-38 induced delayed migraine-like headaches in a large majority of migraine patients has resulted in considerable excitement in headache research
The term “neurogenic inflammation” (NI) has been applied in migraine research and was originally defined as a physiological mechanism resulting in dilation, plasma protein extravasation (PPE)evoked oedema, mast cell degranulation, as well as other manifestations mediated by the release of neuropeptides from peripheral and central afferent nerve terminals
Summary
The discovery that intravenous (IV) infusions of the neuropeptide PACAP-38 (pituitary adenylyl cyclase activating peptide-38) induced delayed migraine-like headaches in a large majority of migraine patients has resulted in considerable excitement in headache research. The term “neurogenic inflammation” (NI) has been applied in migraine research and was originally defined as a physiological mechanism resulting in dilation, plasma protein extravasation (PPE)evoked oedema, mast cell degranulation, as well as other manifestations mediated by the release of neuropeptides from peripheral and central afferent nerve terminals. Support for this mechanism in migraine is predominantly based on animal studies, and historically revolves around mainly dural-mediated mechanisms. Several drug classes screened as potential acute migraine therapeutics, defined by their ability to inhibit dural PPE, including specific extravasation inhibitors (i.e., conformationally restricted analogues of triptans) [42, 118], neurokinin 1 receptor antagonists [60, 61], and inducible nitric oxide synthase inhibitors [72], were all ineffective clinically as either acute or preventive treatments
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