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 alpha(i) 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. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.