Vol.:(0123456789) 1 3 Archives of Dermatological Research (2018) 310:165–172 https://doi.org/10.1007/s00403-018-1809-9 ORIGINAL PAPER Attenuation of serotonin-induced itch by sumatriptan: possible involvement of endogenous opioids Nazgol‑Sadat Haddadi 1,2  · Arash Foroutan 1,2  · Saeed Shakiba 1,2  · Khashayar Afshari 1,2  · Sattar Ostadhadi 2,3  · Maryam Daneshpazhooh 4  · Ahmad‑Reza Dehpour 1,2,3 Received: 13 November 2017 / Revised: 23 December 2017 / Accepted: 12 January 2018 / Published online: 19 January 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Serotonin (5-hydroxytryptamine or 5-HT) is a neurotransmitter in itch and impaired serotonin signaling has been linked to a variety of itch conditions. Intradermal injection of 5-HT induces scratching behavior in mice through stimulation of 5-HT receptors. Previous studies have demonstrated that selective 5-HT1B/1D receptors agonists, including sumatriptan, inhibits neurotransmission. We have also reported that sumatriptan suppresses chloroquine-induced itch. Therefore, we investigated if sumatriptan has inhibitory efects on serotonin-induced itch in mice. Here, we show that intradermal and intraperitoneal administration of sumatriptan signifcantly reduce 5-HT-induced scratching behavior in mice. While intradermal injection of GR-127935, a selective 5-HT1B/1D receptors antagonist, reverses the anti-pruritic efects of sumatriptan. In addition, we show that intradermal and intraperitoneal naltrexone (NTX), a non-specifc opioid receptor antagonist, and methylnaltrexone (MNTX), a peripherally acting opioid receptor antagonist, signifcantly decrease the 5-HT-induced scratching behavior. Addi- tionally, combined treatment with sub-efective doses of sumatriptan and an opioid receptor antagonist, naltrexone, decreases 5-HT-evoked scratching responses. We conclude that sumatriptan inhibits 5-HT-induced itch by activating the peripheral 5-HT1B/1D receptors. Moreover, peripheral opioid receptors have a role in serotonin-induced itch, and anti-pruritic efects of sumatriptan seem to involve the opioid system. These data suggest that 5-HT1B/1D receptors agonists maybe useful to treat a variety of pathologic itch conditions with impaired serotonergic system. Keywords Itch · Sumatriptan · 5-HT1B/1D serotonin receptors · Opioid · Mice Introduction Pruritus (itch) is an irritating sensation triggering a desire to scratch [3]. Serotonin, an infammatory mediator, is secreted from skin mast cells, platelets and melanocytes [28, 45, 49], participates in acute and chronic itch [50] mediated by the histamine-independent pathway [23]. The impaired seroton- ergic system is also associated with a variety of pruritic skin diseases and systemic disorders including atopic dermatitis, psoriasis, allergy, uremia, and cholestasis [39]. Serotonin directly activates 5-HT receptors on sensory neurons to evoke itch [20]. Consistent with non-histaminergic nature of serotonin-induced itch, antihistamines are not efective to reduce it. A variety of 5-HT receptors subtypes express- ing in sensory nerves participate in itch pathway including 5-HT2, 5-HT3, and 5-HT7 receptors. It has been reported that ondansetron and tropisetron, the 5-HT3 antagonists, reduce 5-HT-induced scratching responses in mice [40]. However, some previous studies have shown that 5-HT3 Deceased: Sattar Ostadhadi in 10/2017. * Ahmad-Reza Dehpour dehpour@yahoo.com; dehpoura@sina.tums.ac.ir 1 Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran 2 Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran 3 Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran 4 Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran