Suppression by the sumatriptan analogue, CP-122,288 of c-fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin.
1. The effects of an intravenously administered sumatriptan analogue were examined on c-fos-like immunoreactivity (c-fos-LI), a marker of neuronal activation, evoked within trigeminal nucleus caudalis (TNC) and other brain stem regions 2 h after intracisternal injection of the irritant, capsaicin (0.1 ml, 0.1 mM), in pentobarbitone-anaesthetized Hartley guinea-pigs. 2. C-fos-LI was assessed in eighteen serial sections (50 microns) using a polyclonal antiserum. A weighted average, reflecting total expression within lamina I, IIo of TNC was obtained from three representative levels (i.e., at -0.225 mm, -2.475 mm and -6.975 mm.). 3. Capsaicin caused significant labelling within lamina I, IIo, a region containing axonal terminations of small unmyelinated C-fibres, as well as within the nucleus of the solitary tract, area postrema and medial reticular nucleus. A similar distribution of positive cells was reported previously after intracisternal injection of other chemical irritants such as autologous blood or carrageenin. 4. Pretreatment with a conformationally restricted sumatriptan analogue (with some selectivity for 5-HT1B and 5-HTID receptor subtypes) CP-122,288, reduced the weighted average by approximately 50-60% (P < 0.05) in lamina I, IIo at > or = 100 pmol kg-1, i.v., but did not decrease cell number within area postrema, nucleus of the solitary tract or medial reticular nucleus. A similar pattern was reported previously following sumatriptan, dihydroergotamine or CP-93,129 administration after noxious meningeal stimulation. 5. We conclude that modifications at the amino-ethyl side chain of sumatriptan dramatically enhance the suppression of c-fos expression within TNC, a finding consistent with its remarkable potency against neurogenic plasma protein extravasation within dura mater. CP-122,288 and related analogues may serve as an important prototype for drug development in migraine and related headaches.
Cutrer
F M
FM
Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Schoenfeld
D
D
Limmroth
V
V
Panahian
N
N
Moskowitz
M A
MA
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002211:Capsaicin / Q000008:administration & dosage / Q000494:pharmacology*; D002946:Cisterna Magna; D003864:Depression, Chemical; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007267:Injections; D008297:Male; D009619:Nociceptors / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D011759:Pyrrolidines / Q000494:pharmacology*; D015656:Respiratory Mechanics / Q000187:drug effects; D018170:Sumatriptan / Q000031:analogs & derivatives* / Q000494:pharmacology; D012668:Trigeminal Ganglion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D016760:Proto-Oncogene Proteins c-fos; D011759:Pyrrolidines; C085263:CP 122288; D018170:Sumatriptan; D002211:Capsaicin