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.