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

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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 μm) 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-HT1D receptor subtypes) CP-122,288, reduced the weighted average by approximately 50–60% (Po at ≥ 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.