SUMATRIPTAN AND MOH: DIFFERENTIAL 5-HT1R SIGNALING IN TRIGEMINAL NOCICEPTORS

Migraine is a collection of neurological symptoms that include recurring, intense, throbbing headache pain thatcan last from 4 to 72 hours and affects millions of people. The discovery of the triptan drugs was a majorbreakthrough for the treatment of debilitating pain for many migraine sufferers. Unfortunately, repeated orprolonged use of triptans and other analgesic drugs (e.g. opioids, ergotamines) often results in production of aserious, disabling adverse effect known as medication overuse headache (MOH). The mechanisms thatunderlie development of MOH are not well-understood, but it appears that prolonged treatment withantimigraine medications, like triptans, promote pro-nociceptive changes in primary peripheral pain-sensingneurons (nociceptors) of the trigeminal ganglion (TG). Such neuroadaptive changes in peripheral nociceptorsare thought to contribute to the induction and maintenance of additional modifications in the CNS that lead tolong-term increases in pain sensation and MOH. However, little is known of the effects of prolongedapplication of antimigraine drugs on peripheral nociceptor function. Triptans, such as the prototypicalantimigraine drug sumatriptan, are agonists for 5-hydroxytryptamine1B (5-HT1B), 5-HT1D and 5-HT1F receptorsubtypes. Recent advances in our understanding of drug-receptor interactions and desensitization suggest apossible mechanism for triptan-induced MOH. It is known that receptors can regulate the activity of severalcellular signal transduction pathways and studies demonstrate that desensitization (reduced function) is notuniform across all signaling pathways. Some pathways desensitize more, or less, than others. Furthermore,prolonged agonist treatment can cause a receptor to couple to a different and opposing signaling pathway(signal switching). We hypothesize that following prolonged triptan use for migraine treatment, 5-HT1receptor-mediated signaling in TG nociceptors differentially desensitizes such that inhibitory pathwaysresponsible for analgesia are less active (desensitized), but other excitatory cellular signalingpathways that lead to activation/sensitization of pain-sensing neurons and pain sensation (headache)are more efficiently activated. Differential desensitization and/or signal switching may also underlie effects ofprolonged treatment with other antimigraine drugs (e.g. opioids, ergotamines) that result in MOH. In thisexploratory R21 application we propose to test the hypothesis that prolonged sumatriptan treatment of rats andmice induces differential desensitization/signal switching of inhibitory (G?i) versus excitatory (G?s,extracellular signal-regulated kinase, and/or nitric oxide) signaling coupled to 5-HT1B/1D/1F receptors intrigeminal nociceptors. Results of these experiments will provide the first information about changes innociceptor receptor function that contribute to the induction and/or maintenance of MOH following triptantreatment for migraine. This information will aid in development of improved drugs, devoid of the propensity toinduce MOH, for the effective treatment of migraine.