Release of immunoreactive substance P in the brain stem upon stimulation of the cranial dura mater with low pH - inhibition by the serotonin (5-HT1) receptor agonist CP 93,129.

Abstract

1. The therapeutical benefit of serotonin (5-HT1) receptor agonists in the treatment of migraine headache has been attributed to their inhibitory effect on the release of pro-inflammatory neuropeptides from trigeminal afferents within the cranial meninges. The effect of 5-HT1 receptor agonists on the release of neuropeptides from central afferent terminals has not been examined so far. In the present study in the rat we therefore measured the effect of the 5-HT1B receptor agonist CP 93,129 on the stimulation-evoked release of immunoreactive substance P (ir-SP) in the spinal trigeminal nucleus. 2. To measure release of ir-SP, microprobes coated with antibody to substance P were inserted into the medulla oblongata at the level of the obex. The ipsilateral parietal dura mater encephali was exposed and stimulated with acid phosphate buffered Tyrode solution (pH 5.8). This chemical stimulus increased the release of ir-SP in the medullary dorsal horn. 3. Systemic (i.v.) administration of CP 93,129 (460 nmol kg(-1)) prior to stimulation suppressed the stimulation-evoked increase of release of ir-SP. Local administration of CP 93,129 (10 microM) to the dorsal surface of the medulla had no significant inhibitory effect on the release. 4. It is concluded that systemically applied 5-HT1 receptor agonists reduce the stimulation-evoked release of substance P from the central endings of meningeal afferents in the spinal trigeminal nucleus (medullary dorsal horn). This inhibitory effect may contribute to the antinociceptive effect of 5-HT1 receptor agonists in migraine.