Effects of Acute or Chronic Administration of Anti-Migraine Drugs Sumatriptan and Zolmitriptan on Serotonin Synthesis in the Rat Brain

Abstract

Triptans are 5-HT1 receptor agonists used as anti-migraine drugs. They act primarily on meningeal blood vessels and on trigeminovascular afferents, but they may also exert central effects. We studied the regional effects of acute and chronic treatment with sumatriptan or zolmitriptan on the rate of serotonin (5-HT) synthesis in the rat brain, using the alpha-14C-methyl-L-tryptophan quantitative autoradiographic method. Sumatriptan at low (300 microg/kg, s.c.) and high (1 mg/kg) doses, as well as zolmitriptan (100 microg/kg), acutely decreased (15-40%, P < 0.05-0.001) 5-HT synthetic rate in many brain regions, including the dorsal raphe nucleus. Chronically, sumatriptan (21 days, approximately 300 microg/kg per day via osmotic minipumps) induced significant increases in the 5-HT synthesis rate in many projection areas but had no effect in the dorsal raphe nucleus. The acute effects on 5-HT synthesis rate would be compatible with activation of 5-HT1 autoreceptors that inhibit serotonin release. In contrast, the increased 5-HT synthesis rate observed after chronic sumatriptan might possibly result from a down-regulation/desensitization of 5-HT1 receptors and/or unmasking of excitatory triptan-sensitive 5-HT receptors. Overall, the present findings indicate that not only zolmitriptan but also sumatriptan affect brain serotonergic neurotransmission.

Medication overuse headache

“…This may occur as early as 24 -96 hours after chronic exposure [40]. Chronic administration of sumatriptan and zolmitriptan also caused a decrease of the 5-HT 1B/D synthesis [41,42] and may subsequently change central inhibitory and antinociceptive pathways. An upregulation of pro-nociceptive 5-HT 2A receptors was observed in platelets of patients with drug-induced headache [43].…”

Pathophysiology of Medication-overuse Headache: Implications from Animal Studies

“…The increase in CSD susceptibility observed in rats with chronic acetaminophen exposure was blocked by 5-HT 2A receptor antagonist [17••]. Alteration of the 5-HT receptor and transporter expression in several subcortical areas, including the periaqueductal grey and the locus coeruleus, also has been reported in animals with chronic triptan exposure [18,19]. Both areas have important roles in regulating the nociception and other vegetative functions such as alertness and autonomic functions, among others.…”

Trigeminal Pain Molecules, Allodynia, and Photosensitivity Are Pharmacologically and Genetically Modulated in a Model of Traumatic Brain Injury

“…37 Sumatriptan is a migraine therapeutic, a serotonin (5-HT1) agonist, and reduces the release of CGRP from trigeminal ganglia neurons. 38,39 Doses for MK8825 37 and sumatriptan 28,40 were selected based on the literature and pilot studies in our laboratory. Treatments were administered on 2 consecutive days in postoperative week 2, on days 13 and 14 before euthanasia.…”