The 5-HT1 receptors inhibiting the rat vasodepressor sensory CGRPergic outflow: Further involvement of 5-HT1F, but not 5-HT1A or 5-HT1D, subtypes

We have previously shown that 5-HT1B receptors inhibit prejunctionally the rat vasodepressor CGRPergic sensory outflow. Since 5-HT1 receptors comprise 5-HT1A, 5-HT1B, 5-HT1D and 5-HT1F functional subtypes, this study has further investigated the role of 5-HT1A, 5-HT1D and 5-HT1F receptor subtypes in the inhibition of the above vasodepressor sensory outflow. Pithed rats were pretreated with i.v. continuous infusions of hexamethonium and methoxamine, followed by 5-HT1 receptor agonists. Then electrical spinal stimulation (T9–T12) or i.v. bolus injections of exogenous α-CGRP produced frequency-dependent or dose-dependent vasodepressor responses. The electrically-induced vasodepressor responses remained unchanged during infusions of the 5-HT1A receptor agonists 8-OH-DPAT and NN-DP-5-CT. In contrast, these responses were inhibited by the agonists sumatriptan (5-HT1A/1B/1D/1F), indorenate (5-HT1A), PNU-142633 (5-HT1D) or LY344864 (5-HT1F), which did not affect the vasodepressor responses to exogenous CGRP (implying a prejunctional sensory-inhibition). When analysing the effects of antagonists: (i) 310 μg/kg (but not 100 μg/kg) GR127935 (5-HT1A/1B/1D/1F) abolished the inhibition to sumatriptan, indorenate, PNU-142633 or LY344864; (ii) 310 μg/kg SB224289 (5-HT1B) or BRL15572 (5-HT1D) failed to block the inhibition to sumatriptan or PNU-142633, whereas SB224289 + BRL15572 partly blocked the inhibition to sumatriptan; and (iii) 10 μg/kg WAY100635 (5-HT1A) failed to block the inhibition to indorenate. These results suggest that 5-HT1F, but not 5-HT1A or 5-HT1D, receptor subtypes inhibit the vasodepressor sensory CGRPergic outflow although, admittedly, no selective 5-HT1F receptor agonist is available yet. The pharmacological profile of these receptors resembles that shown in rat dorsal root ganglia by molecular biology techniques.