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

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. C‐fos‐LI was assessed in eighteen serial sections (50 μm) using a polyclonal antiserum. A weighted average, reflecting total expression within lamina I, II_o of TNC was obtained from three representative levels (i.e., at −0.225 mm, −2.475 mm and −6.975 mm.) Capsaicin caused significant labelling within lamina I, II_o, 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. Pretreatment with a conformationally restricted sumatriptan analogue (with some selectivity for 5‐HT_1B and 5‐HT_1D receptor subtypes) CP‐122,288, reduced the weighted average by approximately 50–60% (P<0.05) in lamina I, II_o 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. 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. 1995 British Pharmacological Society