Marked sexual dimorphism in 5-HT₁ receptors mediating pronociceptive effects of sumatriptan

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-HT_1B), but not 5-HT_1D, markedly inhibited sumatriptan (1pg)-induced hyperalgesia, at 10ng a 5-HT_1D receptor antagonist completely eliminated hyperalgesia. In contrast, in females, the 5-HT_1D, but not 5-HT_1B, receptor antagonist completely blocked sumatriptan (1pg and 10ng) hyperalgesia and both 5-HT_1B and 5-HT_1D receptor antagonists attenuated hyperalgesia (1ng) in females, which is GPR30 estrogen receptor dependent. While selective 5-HT_1D or 5-HT_1B, 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 α_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.