The role of 5-HT1B and 5-HT1D receptors in the selective inhibitory effect of naratriptan on trigeminovascular neurons.

The importance of 5-HT(1B) and 5-HT(1D) receptors in the actions of the anti-migraine drug naratriptan was investigated using the relatively selective 5-HT(1) receptor ligands SB224289 and BRL15572. Electrical stimulation of the superior sagittal sinus (SSS) in cats activated neurones in the trigeminal nucleus caudalis. Facial receptive fields (RF) were also electrically stimulated to activate the same neurones. Responses of these neurones to SSS stimulation were suppressed by iontophoretic application of naratriptan (5-50 nA). There were two distinct populations of neurones in the nucleus--those in deeper laminae in which the responses to SSS and RF stimulation were equally suppressed by naratriptan ('non-selective') and more superficial neurones in which only the SSS responses were suppressed by naratriptan ('selective'). Concurrent micro-iontophoretic application (50 nA) of the 5-HT(1D) antagonist BRL15572 antagonised the suppression by naratriptan of the response of 'selective' cells to SSS stimulation. Iontophoretic application of SB224289 (50 nA), a 5-HT(1B) antagonist, antagonised the suppression by naratriptan of responses of 'non-selective' cells to RF stimulation and, to a lesser extent, also antagonised the suppression of responses to SSS stimulation. Intravenous administration of SB224289 antagonised the suppression only of RF responses of "non-selective" neurons by naratriptan and intravenous administration of BRL15572 antagonised the suppression only of SSS responses of "selective" neurons by naratriptan. These results suggest that the response of nucleus caudalis neurons to stimulation of the sagittal sinus can be modulated by both 5-HT(1B) and 5-HT(1D) receptor activation, with the 5-HT(1D) receptors perhaps playing a greater role. The response to RF stimulation is more influenced by 5-HT(1B) receptor modulation with 5-HT(1D) receptors being less important. Therefore, this suggests that selective 5-HT(1D) agonists may be able to target the neuronal population, which is selectively involved in the transmission of dural inputs. We conclude that the central terminals of trigeminal primary afferent fibres contain 5-HT(1B) and 5-HT(1D) receptors. Primary afferents from the dura mater may predominantly express 5-HT(1D) receptors, while facial afferents may predominantly express 5-HT(1B) receptors. Activation of 5-HT(1D) receptors in particular may be important in the anti-migraine effect of naratriptan.