The development and use of
serotonin-1B/1D agonists to treat the acute attack of
migraine has been a significant advance, but their
vasoconstrictor effects have lead to a search for non-
vasoconstrictor approaches to the management of the acute attack of
migraine. One such suggested approach has been
substance P (neurokinin-1) antagonists, since
substance P is involved in mediating neurogenic
plasma protein extravasation and has long been held to have a role in
pain transmission. In this study, one such candidate compound,
GR205171, a highly lipophilic potent neurokinin-1 antagonist, has been tested in a model of trigeminovascular nociception with considerable predictive value for anti-
migraine activity. The superior sagittal sinus was isolated in the
alpha-chloralose (60 mg/kg, i.p., and 20 mg/kg, i.v., supplemented every 2 h)-anaesthetized cat. The sinus was stimulated electrically (100 V, 250 micros duration, 0.3 Hz) and neurons in the dorsal C2 spinal cord monitored using electrophysiological methods. In separate experiments, the animals were prepared for stimulation and then maintained for 24 h before stimulation and perfusion for Fos immunohistochemistry. Stimulation of the superior sagittal sinus resulted in activation of cells in the dorsal horn of C2. Cells fired with a probability of 0.7 +/- 0.1 at a latency of 10.7 +/- 0.2 ms. Administration of
GR205171 (100 microg/kg, i.v.) had no effect on probability of firing or latency. Stimulation of the sinus in separate cats resulted in increased expression over control levels in the superficial laminae of the trigeminal nucleus caudalis and C1/2 dorsal horns.
GR205171 in the same dose had no effect upon Fos expression. Inhibition of
substance P by the potent, selective and brain penetrant neurokinin-1 antagonist
GR205171 had no effect upon either cell firing or Fos expression in the central trigeminal cells activated by stimulation of the superior sagittal sinus. These data and the published clinical data for other compounds suggest that neurokinin-1 blockade alone will not be an effective anti-
migraine strategy. Further data will be required to assess whether neurokinin-1 antagonists will have any more general value in
pain.