title: Marked sexual dimorphism in 5-HT1receptors mediating pronociceptive effects of sumatriptan.
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 10fg to 1000ng (intradermal) of sumatriptan induced a complex dose-dependent mechanical hyperalgesia in male rats, with distinct peaks, at 1pg and 10ng, but no hyperalgesia at 1ng. In contrast, in females, there was 1 broad peak. The highest dose (1000ng) did not produce hyperalgesia in either sex. We evaluated the receptors mediating sumatriptan hyperalgesia (1pg, 1 and 10ng). In males, the injection of an antagonist for the serotonin (5-HT) receptor subtype 1B (5-HT1B), but not 5-HT1D, markedly inhibited sumatriptan (1pg)-induced hyperalgesia, at 10ng a 5-HT1Dreceptor antagonist completely eliminated hyperalgesia. In contrast, in females, the 5-HT1D, but not 5-HT1B, receptor antagonist completely blocked sumatriptan (1pg and 10ng) hyperalgesia and both 5-HT1Band 5-HT1Dreceptor antagonists attenuated hyperalgesia (1ng) in females, which is GPR30 estrogen receptor dependent. While selective 5-HT1Dor 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 (1pg and 10ng) is dependent on the G-protein αisubunit 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.
authors.affiliation: Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA 94143-0440, United States; Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143-0440, United States.
authors.forename: Dioneia
authors.initials: D
authors.lastname: Araldi
authors.affiliation: Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA 94143-0440, United States; Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143-0440, United States.
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Ferrari
authors.affiliation: Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA 94143-0440, United States; Department of Preventative & Restorative, University of California at San Francisco, San Francisco, CA 94143-0440, United States; Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143-0440, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Green
authors.affiliation: Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA 94143-0440, United States; Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143-0440, United States. Electronic address: Jon.Levine@ucsf.edu.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Levine
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism*; D044346:Receptor, Serotonin, 5-HT1D / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000633:toxicity; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D012727:Sex Characteristics; D018170:Sumatriptan / Q000633:toxicity*; D014110:Touch
chemical_list: C520305:Gper1 protein, rat; D012333:RNA, Messenger; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D043562:Receptors, G-Protein-Coupled; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D018170:Sumatriptan; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: 5-HT(1B) receptor; 5-HT(1D) receptor; hyperalgesia; migraine; triptans