Gi-protein–coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming. Issue 8 (August 2016)

• Record Type: Journal Article
• Authors: Araldi, Dioneia; Ferrari, Luiz F.; Levine, Jon D.
• Is Part Of: Pain. Volume 157:Issue 8(2016)
• Publication Date: 2016-08
• Subjects: Hyperalgesic priming -- Hyperalgesia -- 5-HT1B receptor -- 5-HT1D receptor -- GPCRs -- Chronic pain -- Triptans; Pain -- Periodicals; Douleur -- Périodiques; Anesthésie -- Périodiques; Pain; Electronic journals; Periodicals; Electronic journals; 616.0472
• DOI: 10.1097/j.pain.0000000000000581
• Languages: English
• ISSNs: 0304-3959

Abstract

Abstract : Abstract: We have recently described a novel form of hyperalgesic priming (type II) induced by agonists at two clinically important Gi-protein–coupled receptors (Gi-GPCRs), mu-opioid and A1-adenosine. Like mu-opioids, the antimigraine triptans, which act at 5-HT1B/D Gi-GPCRs, have been implicated in pain chronification. We determined whether sumatriptan, a prototypical 5-HT1B/D agonist, produces type II priming. Characteristic of hyperalgesic priming, intradermal injection of sumatriptan (10 ng) induced a change in nociceptor function such that a subsequent injection of prostaglandin-E2 (PGE2 ) induces prolonged mechanical hyperalgesia. However, onset to priming was delayed 3 days, characteristic of type I priming. Also characteristic of type I priming, a protein kinase Cε, but not a protein kinase A inhibitor attenuated the prolongation phase of PGE2 hyperalgesia. The prolongation of PGE2 hyperalgesia was also permanently reversed by intradermal injection of cordycepin, a protein translation inhibitor. Also, hyperalgesic priming did not occur in animals pretreated with pertussis toxin or isolectin B4–positive nociceptor toxin, IB4–saporin. Finally, as observed for other agonists that induce type I priming, sumatriptan did not induce priming in female rats. The prolongation of PGE2 hyperalgesia induced by sumatriptan was partially prevented by coinjection of antagonists for the 5-HT1B and 5-HT1D, but not 5-HT7, serotonin receptors and completely prevented by coadministration of a combination of the 5-HT1B and 5-HT1D antagonists. Moreover, the injection of selective agonists, for 5-HT1B and 5-HT1D receptors, also induced hyperalgesic priming. Our results suggest that sumatriptan, which signals through Gi-GPCRs, induces type I hyperalgesic priming, unlike agonists at other Gi-GPCRs, which induce type II priming. Abstract : This study investigates the intracellular mechanisms involved in the hyperalgesic priming, a preclinical model of chronic pain, induced by activation of the Gi-protein–coupled receptors 5-HT1B and 5-HT1D, by sumatriptan.