Immunohistochemical localization of a vasodilatory polypeptide (VIP) in cerebrovascular nerves

Migraine treatment has reached a new era with the development of drugs that target the trigeminal neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. The CGRP related therapies offer considerable improvements over existing drugs as they are the first to be designed to act on the trigeminal pain system, more specific and with few adverse events. Small molecule CGRP receptor antagonists, such as rimegepant and ubrogepant, are effective for the acute treatment of migraine headache. In contrast, monoclonal antibodies against CGRP or the CGRP receptor are beneficial for the prophylactic treatments in chronic migraine. Here I will provide a historical overview of the long path that led to their successful development. In addition, I will discuss aspects on the biology of CGRP signalling, the role of CGRP in migraine headache, the efficacy of CGRP targeted treatment, and synthesize what currently is known about the role of CGRP in the trigeminovascular system.

In Primary Headache Disorders, Part 1, we discuss three of the primary headache disorders using the headache definitions from ICHD-III (Beta): Migraine, with and without aura; its pathophysiology and treatment are discussed. We then discuss the Trigeminal Autonomic Cephalalgias (TACs), including Cluster Headache and Hemicrania Continua, two more primary headache disorders, as well as the other TAC Headaches. We discuss pathophysiology as well as diagnosis, treatment, and pharmacotherapeutic management of these headache diatheses.

Cerebral circulation is regulated by two principal systems: autonomic and sensory nerves from cranial ganglia and intrinsic innervation of the cerebral microcirculation. The sympathetic innervation originates from the superior cervical ganglion and stores noradrenaline and neuropeptide Y. It has a role in the extreme limits of the autoregulation. The parasympathetic innervation of the brain circulation originates in the sphenopalatine and otic ganglia. This system stores acetylcholine, vasoactive intestinal peptide, pituitary adenylate cyclase–activating peptide, and nitric oxide synthase (NOS). The sensory fibers, involved in cranial pain syndromes, originates in the trigeminal ganglion and stores calcitonin gene-related peptide, substance P, neurokinin A, NOS, and nociceptin, inter alia. Besides these, the intracerebral microcirculation (small arterioles, capillaries, and venules) forms, with the surrounding glial cells and intracerebral neurons, a neurovascular unit that may regulate the cerebral microcirculation.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP) are potent vasodilators in animals and humans. PACAP infusion but not VIP infusion precipitates migraine attacks in migraine patients. The vascular effects of VIP and the two varieties of PACAP (PACAP-27 and PACAP-38) were investigated versus selective antagonists in segments of rat middle cerebral arteries (MCA), basilar arteries (BA) and middle meningeal arteries (MMA) using myographs. The luminal and abluminal effects of VIP were studied using perfusion myograph. mRNA expression of the relevant receptors (VPAC₁, VPAC₂ and PAC₁) was examined by in situ hybridization. There was no significant difference in relaxant potency of the peptides in the MCA. In BA the relaxant potency was VIP > PACAP-27 = PACAP-38. Relaxant responses were either absent or very weak in MMA. VIP was found to be somewhat more potent in BA than in the MCA. Maxadilan, a selective PAC₁-receptor agonist, showed no relaxant effect in either vessel. The VPAC₂-antagonist PG 99-465 alone proved ineffective in the MCA, while it had a weak effect on BA. The VPAC₁-antagonist PG 97-269 inhibited relaxation induced by both VIP and the PACAPs in cerebral vessels. In combination, the two antagonists demonstrated better effect than either alone. VIP applied luminally via perfusion myograph caused no dilatation, indicating lack of endothelial involvement. In situ hybridization demonstrated the presence of mRNA for all three receptors in the smooth muscle cells of the vessels. In conclusion, migraine-like headache induced by PACAP-38 infusion is unlikely to be caused by direct vasodilator action on intracranial vessels.

Vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase activating polypeptides (PACAPs) share 68% identity at the amino acid level and belong to the secretin peptide family. Following the initial discovery of VIP almost four decades ago a substantial amount of knowledge has been presented describing the mechanisms of action, distribution and pleiotropic functions of these related peptides. It is now known that the physiological actions of these widely distributed peptides are produced through activation of three common G-protein coupled receptors (VPAC₁, VPAC₂ and PAC₁R) which preferentially stimulate adenylate cyclase and increase intracellular cAMP, although stimulation of other intracellular messengers, including calcium and phospholipase D, has been reported. Using a range of in vitro and in vivo approaches, including cell-based functional assays, transgenic animals and rodent models of disease, VPAC/PAC receptor activation has been associated with numerous physiological processes (e.g. control of circadian rhythms) and clinical conditions (e.g. pulmonary hypertension), which underlies on-going research efforts and makes these peptides and their cognate receptors attractive targets for the pharmaceutical industry. However, despite the considerable interest in VPAC/PAC receptors and the processes which they mediate, there is still a paucity of selective and available, non-peptide ligands, which has hindered further advances in this field both at the basic research and clinical level. This review summarises the current knowledge of VIP/PACAP and the VPAC/PAC receptors with regard to their distribution, pharmacology, signalling pathways, splice variants and finally, the utility of animal models in exploring their physiological roles.