Differential effects of low dose CP122,288 and eletriptan on Fos expression due to stimulation of the superior sagittal sinus in cat☆

Abstract

CP122,288, a conformationally restricted analogue of sumatriptan, is a highly potent inhibitor of neurogenic plasma protein extravasation (PPE) in rat and guinea pig at low doses where it has no 5HT 1B-mediated vascular actions. We have examined its effect on a model of trigeminovascular nociception to assess the relative importance of vasoconstrictor and serotonin (5HT) IB/lD agonist activity to the modulation trigeminal neuronal activation. For comparison to activate relevant 5HT receptors, the clinically effective relatively lipophilic 5HT IB/ID agonist eletriptan was studied in parallel. The superior sagittal sinus was isolated in the α-chloralose (60 mg/kg, i.p. and 15–20 mg/kg i.v. supplement every 2 h) anaesthetized cat. Animals were prepared for stimulation and then maintained for 24 h before stimulation and perfusion for Fos immunohistochemistry. Stimulation of the superior sagittal sinus (250 μs, 100 V, 0.3 Hz) resulted in Fos expression in cells in the trigeminal nucleus caudalis and superficial laminae of the dorsal horns of C 1–2. Administration of low dose CP122,288 (100 ng/kg) had no effect on Fos expression after sinus stimulation either when administered alone or in combination with mannitol; the latter to ensure access to the trigeminocervical complex. The number of cells in the superficial laminae of the trigeminal nucleus caudalis with stimulation being a median of 50 (quartile range: 47–53) and 48 (35–48) after CP122,288, and after CP122,288 and mannitol 45 (41–53). In comparison, the clinically effective 5HT IB/lD agonist, eletriptan, reduced Fos expression in the trigeminocervical complex to a median of 24 (21–33). These data demonstrate that the potent inhibitor of neurogenic plasma protein extravasation (PPE) CP122,288 has no effect on Fos expression in central trigeminal neurons when administered at a dose which blocks PPE in rat and guinea pig, but has no vasoconstrictor 5HT IB/lD activity, and while ensuring its access to central trigeminal neurons. The data suggest that activation of the 5HT IB/lD receptor is important for the clinical action of this class of compounds and is consistent with the fact the CP122,288 is ineffective in the treatment of the acute attack of migraine.