Prolonged Sumatriptan Treatment Differentially Alters 5HT1 Receptor‐mediated Signaling In Rat Trigeminal Ganglion
Authors: Debner Emily Katherine , Jennings Elaine , Chavera Teresa , Clarke William , Berg Kelly 
Published: June 2021

Medication Overuse Headache (MOH) is caused by repeated use of analgesics, such as triptans, which are used to treat migraines. Triptans are agonists at serotonin (5‐HT) type 1 receptors (5‐HT1B, 5‐HT1D, and 5‐HT1F), which are G protein‐coupled receptors known to couple to both Gi protein‐dependent (e.g., inhibition of cAMP production) and Gi protein‐independent (e.g., extracellular signal regulated kinase, ERK) signaling. Activation of 5HT1 receptors by triptans produce relief of migraine pain largely by inhibiting peripheral pain sensing neurons (nociceptors) of the trigeminal ganglia. However, the mechanism by which repeated/prolonged use of triptans causes MOH is unknown. We hypothesize that repeated or prolonged triptan exposure alters 5‐HT1 receptor‐mediated signaling from inhibitory to excitatory as a result of differential desensitization and/or signal switching in nociceptors. In this study, we examined the effects of prolonged treatment with the prototypical triptan, sumatriptan, on 5‐HT1 receptor‐mediated inhibition of PGE2‐stimulated cAMP accumulation and activation of ERK in rat trigeminal ganglia (TG) primary cultures.Incubation of TG cultures with the 5‐HT1 receptor agonists, 5‐carboxamidotryptamine (5‐CT) or sumatriptan (SUMA) produced a dose dependent inhibition of PGE2‐stimulated cAMP accumulation with an EC50 of 7.7 nM and 6.8 nM and a maximal inhibition of 59% and 45% for 5‐CT and SUMA, respectively. Pretreatment of TG cultures for 24h with SUMA (1 μM) followed by a rigorous washout step had no effect on the ability of 5‐CT to inhibit PGE2‐stimulation of cAMP accumulation. By contrast, rather than an inhibition of cAMP accumulation, SUMA increased PGE2‐mediated cAMP accumulation in TG cultures pretreated for 24h with SUMA suggesting that a switch from 5‐HT1 receptor‐mediated activation of Gi‐ to Gs‐proteins may have occurred. Although both 5‐CT and SUMA increased ERK activity by 40% above basal within 5 min of incubation, by contrast to effects on cAMP signaling, ERK activation in response to 5‐CT was lost whereas responses to SUMA were unaltered in TG cultures pretreated 24h with SUMA. Interestingly, similar to effects on SUMA‐mediated signaling, following 24h pretreatment with SUMA, 5‐HT‐mediated ERK activation was unaltered whereas 5‐HT‐mediated inhibition of cAMP accumulation was no longer observedThese results support our hypothesis that prolonged exposure to a triptan may produce MOH by inducing differential desensitization of 5‐HT1 receptor signaling pathways and signal switching in nociceptors. Future experiments will determine if repeated in vivo administration of sumatriptan will similarly alter 5‐HT1 receptor signaling in rat trigeminal ganglia nociceptors.Support or Funding InformationSupported by NIH/NINDS R21 NS094488 and NIH/T32 NS082145This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.