Marked sexual dimorphism in 5-HT1 receptors mediating pronociceptive effects of sumatriptan. (6th March 2017)

• Record Type: Journal Article
• Authors: Araldi, Dioneia; Ferrari, Luiz F.; Green, Paul; Levine, Jon D.
• Is Part Of: Neuroscience. Volume 344(2017)
• Page Start: 394
• Page End: 405
• Publication Date: 2017-03-06
• Subjects: 5-HT 5-hydroxytryptamine -- 5-HT1B 5-hydroxytryptamine receptor subtype 1B -- 5-HT1D 5-hydroxytryptamine receptor subtype 1D -- PKA protein kinase A -- GPCR G-protein-coupled receptor -- GPR30 G-protein-coupled estrogen receptor 30 -- ANOVA analysis of variance -- CPA N6-Cyclopentyladenosine -- DAMGO [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin; hyperalgesia -- 5-HT1B receptor -- 5-HT1D receptor -- triptans -- migraine; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2016.12.031
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Mechanical hyperalgesia induced by sumatriptan is markedly sexually dimorphic. Sumatriptan produces hyperalgesia by acting on 5-HT1B and/or 5-HT1D receptors. Sumatriptan hyperalgesia in female rats is dependent on estrogen and GPR30. G-protein αi subunit and PKA play a role in sumatriptan hyperalgesia. Sumatriptan hyperalgesia is mediated by IB4-positive and negative nociceptors. Abstract: Amongst the side effects of triptans, a substantial percentage of patients experience injection site pain and tenderness, the underlying mechanism of which is unknown. We found that the dose range from 10 fg to 1000 ng (intradermal) of sumatriptan induced a complex dose-dependent mechanical hyperalgesia in male rats, with distinct peaks, at 1 pg and 10 ng, but no hyperalgesia at 1 ng. In contrast, in females, there was 1 broad peak. The highest dose (1000 ng) did not produce hyperalgesia in either sex. We evaluated the receptors mediating sumatriptan hyperalgesia (1 pg, 1 and 10 ng). In males, the injection of an antagonist for the serotonin (5-HT) receptor subtype 1B (5-HT1B ), but not 5-HT1D, markedly inhibited sumatriptan (1 pg)-induced hyperalgesia, at 10 ng a 5-HT1D receptor antagonist completely eliminated hyperalgesia. In contrast, in females, the 5-HT1D, but not 5-HT1B, receptor antagonist completely blocked sumatriptan (1 pg and 10 ng) hyperalgesia and both 5-HT1B and 5-HT1D receptor antagonists attenuated hyperalgesia (1 ng) in females, which is GPR30 estrogen receptor dependent. While selective 5-HT1D or 5-HT1B, agonists produce robust hyperalgesia in female and male rats, respectively, when co-injected the hyperalgesia induced in both sexes was attenuated. Mechanical hyperalgesia induced by sumatriptan (1 pg and 10 ng) is dependent on the G-protein αi subunit and protein kinase A (PKA), in IB4-positive and negative nociceptors. Understanding the mechanisms responsible for the complex dose dependence for triptan hyperalgesia may provide useful information for the design of anti-migraine drugs with improved therapeutic profiles.