Background: Pituitary adenylate cyclase activating peptide-38 (PACAP-38) has been shown to induce migraine in migraineurs, whereas the related peptide vasoactive intestinal peptide (VIP) does not. In the present study we examine the hypothesis that PACAP-38 and its truncated version PACAP-27 but not VIP cause degranulation of mast cells in peritoneum and in dura mater. Methods: The degranulatory effects of PACAP-38, PACAP-27 and VIP were investigated by measuring the amount of N-acetyl-β-hexosaminidase released from isolated peritoneal mast cells and from dura mater attached to the skull of the rat in vitro. In peritoneal mast cells N-truncated fragments of PACAP-38 (PACAP(6–38), PACAP(16–38) and PACAP(28–38)) were also studied. To investigate transduction pathways involved in mast cell degranulation induced by PACAP-38, PACAP-27 and VIP, the phospholipase C inhibitor U-73122 and the adenylate cyclase inhibitor SQ 22536 were used. Results: The peptides induced degranulation of isolated peritoneal mast cells of the rat with the following order of potency: PACAP-38 = PACAP(6–38) = PACAP(16–38) » PACAP-27 = VIP = PACAP(28–38). In the dura mater we found that 10−5 M PACAP-38 was significantly more potent in inducing mast cell degranulation than the same concentration of PACAP-27 or VIP. Inhibition of intracellular mechanisms demonstrated that PACAP-38-induced degranulation is mediated by the phospholipase C pathway. Selective blockade of the PAC1 receptor did not attenuate degranulation. Conclusion: These findings correlate with clinical studies and support the hypothesis that mast cell degranulation is involved in PACAP-induced migraine. PACAP-38 has a much stronger degranulatory effect on rat peritoneal and dural mast cells than VIP and PACAP-27. The difference in potency between PACAP-38- and PACAP-27/VIP-induced peritoneal mast cell degranulation is probably not related to the PAC1 receptor but is caused by a difference in efficacy on phospholipase C.

The direct vasodilatory effect of VIP and PACAP might be less relevant than the central effect of this compound in migraine pathogenesis.

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Background and purpose: Dilatation of cerebral and dural arteries causes a throbbing, migraine-like pain, indicating that these structures are involved in migraine. Clinical trials suggest that adenosine 5 0 -triphosphate-sensitive K þ (K ATP ) channel opening may cause migraine by dilatating intracranial arteries, including the middle meningeal artery (MMA). We studied the K ATP channel expression profile in rat MMA and examined the potential inhibitory effects of the K ATP channel blocker PNU-37883A on K ATP channel opener-induced relaxation of the rat MMA, using the three K ATP channel openers levcromakalim, pinacidil and P-1075. Experimental approach: mRNA and protein expression of K ATP channel subunits in the rat MMA were studied by quantitative real-time PCR and western blotting, respectively. The in vivo and in vitro effects of the K ATP channel drugs on rat MMA were studied in the genuine closed cranial window model and in myograph baths, respectively. Key results: Expression studies indicate that inwardly rectifying K þ (Kir)6.1/sulphonylurea receptor (SUR)2B is the major K ATP channel complex in rat MMA. PNU-37883A (0.5 mg kg À1 ) significantly inhibited the in vivo dilatory effect of levcromakalim (0.025 mg kg À1 ), pinacidil (0.38 mg kg À1 ) and P-1075 (0.016 mg kg À1 ) in rat MMA. In vitro PNU-37883A significantly inhibited the dilatory responses of the three K ATP channel openers in rat MMA at 10 À7 and 3 Â 10 À7 M. Conclusions and implications:We suggest that Kir6.1/SUR2B is the major functional K ATP channel complex in the rat MMA. Furthermore, we demonstrate the potent in vivo and in vitro blocking potentials of PNU-37883A on K ATP channel openerinduced relaxation of the rat MMA.

K(ATP) channel openers do not interact with CGRP release or mast cell degranulation. Activation of these channels in the CNS is antinociceptive and therefore cannot explain the headache induced by K(ATP) channel openers. Thus, they are likely to induce headache by interaction with extracerebral K(ATP) channels, probably the SUR2B isoforms.

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Our results suggest that EP(4), and to a lesser degree EP(2), receptors mediate the dilatory effect of PGE(2) in the craniovascular system in rats. Thus, antagonism of these receptors might be of therapeutic relevance in migraine.