Suppression by the sumatriptan analogue, CP-122,288 of c-fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin.

Abstract

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.

• Authors: F M Cutrer, D Schoenfeld, V Limmroth, N Panahian, M A Moskowitz
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 114 Issue 5 Pg. 987-92 (Mar 1995) ISSN: 0007-1188 [Print] England
• PMID: 7780655 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Proto-Oncogene Proteins c-fos
• Pyrrolidines
• CP 122288
• Sumatriptan
• Capsaicin

Topics

• Animals
• Aorta, Thoracic (drug effects)
• Blood Pressure (drug effects)
• Capsaicin (administration & dosage, pharmacology)
• Cisterna Magna
• Depression, Chemical
• Guinea Pigs
• Heart Rate (drug effects)
• Immunohistochemistry
• In Vitro Techniques
• Injections
• Male
• Nociceptors (drug effects)
• Proto-Oncogene Proteins c-fos (biosynthesis)
• Pyrrolidines (pharmacology)
• Respiratory Mechanics (drug effects)
• Sumatriptan (analogs & derivatives, pharmacology)
• Trigeminal Ganglion (cytology, drug effects, metabolism)