Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and its receptors are widely distributed at different levels of the pain-processing pathway. Its action at the peripheral sensory nerve terminals has been found to be divergent; it can exert both pro-and antinociceptive effects, depending on the mode of administration (local or systemic) and the mechanism of the pain process (acute or chronic, inflammatory or neuropathic). In the central nervous system it exerts mainly neuronal

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... n, leading to increased nociceptive signalling. Since the clinical data strongly suggest the involvement of PACAP in the pathophysiology of migraine, special emphasis is placed on examinations of its role and the mechanisms of activation of the trigeminovascular system (TS). The intravenous administration of PACAP to migraineurs induces migraine-like headache and extracranial arterial dilatation. Furthermore, an increased PACAP concentration has been detected in the peripheral blood of patients during a migraine attack. Animal experiments have also revealed that PACAP elicits peripheral and central sensitization of the neuronal elements of the TS and evokes meningeal vasodilatation. This review summarizes data relating to the expression of PACAP and its receptors, and the main effects and mechanisms in the nociceptive pathways, with special emphasis on migraine. It is clear that PACAP plays an excitatory role in migraine, but its target and signalling pathways have not yet been elucidated due to the lack of nonpeptide, selective agonists and antagonists. Identification of its up-and downstream regulations and receptorial molecular mechanisms might open up future perspectives for the development of novel analgesic drugs. Graphical abstract cortex MIGRAINE brainstem vasculature trigeminal ganglion PACAP cortex NOCICEPTION spinal cord dorsal root ganglion Keywords primary sensory neuron, nociception, pain matrix, pituitary adenylate cyclase-activating polypeptide, sensitization, trigeminovascular system, migraine