title: Dural mast cell degranulation is a putative mechanism for headache induced by PACAP-38.
abstract: 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 PAC(1) receptor did not attenuate degranulation.
  
  
  CONCLUSIONS
  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 PAC(1) receptor but is caused by a difference in efficacy on phospholipase C.
authors.affiliation: Department of Neurology, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Baun
authors.forename: Martin Holst Friborg
authors.initials: MH
authors.lastname: Pedersen
authors.forename: Jes
authors.initials: J
authors.lastname: Olesen
authors.forename: Inger
authors.initials: I
authors.lastname: Jansen-Olesen
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004388:Dura Mater / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D008881:Migraine Disorders / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism / Q000494:pharmacology; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D010455:Peptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014665:Vasodilator Agents; D014660:Vasoactive Intestinal Peptide