Role of 5-HT5A and 5-HT1B/1D receptors in the antinociception produced by ergotamine and valerenic acid in the rat formalin test

• Published in: European journal of pharmacology Vol. 781; pp. 109 - 116
• Main Authors: Vidal-Cantú, Guadalupe C., Jiménez-Hernández, Mildred, Rocha-González, Héctor I., Villalón, Carlos M., Granados-Soto, Vinicio, Muñoz-Islas, Enriqueta
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.06.2016
• Subjects: 5-HT1B/1D receptors; 5-HT5A receptors; Analgesics - pharmacology; Animals; Behavior, Animal - drug effects; Ergotamine; Ergotamine - pharmacology; Female; Formaldehyde - adverse effects; Indenes - pharmacology; Inflammatory pain; Nociception - drug effects; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A - metabolism; Receptor, Serotonin, 5-HT1B - metabolism; Receptor, Serotonin, 5-HT1D - metabolism; Serotonin Antagonists - pharmacology; Sesquiterpenes - pharmacology; Valerenic acid; SB-699551; 5-hydroxytriptamine (PubChem CID: 5202); BRL-15572 didydrochloride (PubChem CID: 9891303); Ergotamine; Dimethyl sulphoxide (PubChem CID: 679); SB-224289 hydrochloride (PubChem CID: 3378093); 5-HT5A receptors; Valerenic acid; Inflammatory pain; 5-HT1B/1D receptors; 5-HT(5A) receptors; 5-HT(1B/1D) receptors
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2016.04.009

Sumatriptan, dihydroergotamine and methysergide inhibit 1% formalin-induced nociception by activation of peripheral 5-HT1B/1D receptors. This study set out to investigate the pharmacological profile of the antinociception produced by intrathecal and intraplantar administration of ergotamine (a 5-HT1B/1D and 5-HT5A/5B receptor agonist) and valerenic acid (a partial agonist at 5-HT5A receptors). Intraplantar injection of 1% formalin in the right hind paw resulted in spontaneous flinching behavior of the injected hindpaw of female Wistar rats. Intrathecal ergotamine (15nmol) or valerenic acid (1 nmol) blocked in a dose dependent manner formalin-induced nociception. The antinociception by intrathecal ergotamine (15nmol) or valerenic acid (1nmol) was partly or completely blocked by intrathecal administration of the antagonists: (i) methiothepin (non-selective 5-HT5A/5B; 0.01–0.1nmol); (ii) SB-699551 (selective 5-HT5A; up to 10nmol); (iii) anti-5-HT5A antibody; (iv) SB-224289 (selective 5-HT1B; 0.1–1nmol); or (v) BRL-15572 (selective 5-HT1D; 0.1–1nmol). Likewise, antinociception by intraplantar ergotamine (15nmol) and valerenic acid (10nmol) was: (i) partially blocked by methiothepin (1nmol), SB-699551 (10nmol) or SB-224289 (1nmol); and (ii) abolished by BRL-15572 (1nmol). The above doses of antagonists (which did not affect per se the formalin-induced nociception) were high enough to completely block their respective receptors. Our results suggest that ergotamine and valerenic acid produce antinociception via 5-HT5A and 5-HT1B/1D receptors located at both spinal and peripheral sites. This provides new evidence for understanding the modulation of nociceptive pathways in inflammatory pain.