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 bene®t of serotonin (5-HT 1 ) receptor agonists in the treatment of migraine headache has been attributed to their inhibitory e ect on the release of pro-in¯ammatory neuropeptides from trigeminal a erents within the cranial meninges. The e ect of 5-HT 1 receptor agonists on the release of neuropeptides from central a erent terminals has not been examined so far. In the present study in the rat we therefore measured the e ect of the 5-HT 1B 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 bu ered 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 71 ) prior to stimulation suppressed the stimulation-evoked increase of release of ir-SP. Local administration of CP 93,129 (10 mM) to the dorsal surface of the medulla had no signi®cant inhibitory e ect on the release. 4 It is concluded that systemically applied 5-HT 1 receptor agonists reduce the stimulation-evoked release of substance P from the central endings of meningeal a erents in the spinal trigeminal nucleus (medullary dorsal horn). This inhibitory e ect may contribute to the antinociceptive e ect of 5-HT 1 receptor agonists in migraine.

Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT 1B/1D receptor agonists

“…evidence that sumatriptan represses secretion of these neurotransmitters from central branches of such nociceptors through modulation of intracellular calcium (30)(31)(32).…”

Headache and Pregnancy

“…10 Serotonin depletion can induce migraine and selective serotonin agonists such as the triptans can alleviate the pain of a migraine headache. Substance P, 11,12 neurokinin A, [13][14][15][16][17] calcitonin gene related peptide, [15][16][17] norepinephrine, GABA, and glutamic acid 8,9 play less significant roles. The brain structures where migraine pathology occurs involve the trigeminal pain pathways, 10,[18][19][20][21][22][23][24] brainstem nuclei including the locus ceruleus and dorsal raphe nuclei, 24 -29 the cerebral vasculature, 22-24,28 -32 the thalamus, 10,19,20,33 and the primary sensory cortex.…”

Pathophysiologie der Migräne

“…5-HT 1B/D -Agonisten besitzen neben der peripheren auch eine zentrale Wirkung. Es wurde gezeigt, dass die Applikation eines 5-HT 1B/D -Rezeptoragonisten auf den Hirnstamm die Antworten nozizeptiver trigeminaler Neurone senkt und die Freisetzung von Substanz P aus den zentralen Endigungen der primären Afferenzen reduziert [8,33]. Möglicherwei-se ist die Menge an verfügbarem Serotonin an 5-HT 1B/D -Rezeptoren für die Sensitivität des trigeminovaskulären Systems verantwortlich [8,9].…”