Abstract

The trigeminal system, particularly the afferents innervating the pain-sensitive dura mater, plays a critical role in the pathophysiology of primary headache disorders like migraine. Dopamine (DA) and Tyramine (TYR), both monoamines, are implicated in nociceptive signaling, but their precise mechanisms of action on dural afferents remain incompletely understood. This study investigated the comparative effects of DA and TYR on the electrophysiological activity, specifically the firing rate, of trigeminal dural afferents in wild-type (WT) rats and rats heterozygous for the Dopamine Transporter (DAT-HET). The DAT, a key membrane protein, regulates monoamine homeostasis, and its reduced function in DAT-HET animals provides a model to explore the role of altered monoamine reuptake. Using ex vivo electrophysiological recordings, we found that both DA and TYR significantly increased the firing rate of dural afferents in WT animals, suggesting a pro-nociceptive action. Importantly, the magnitude and duration of the TYR-induced increase in firing rate were significantly enhanced in the DAT-HET rats compared to WT controls. This differential response suggests that the DAT, beyond its primary role in DA reuptake, may also modulate the action of trace amines like TYR on peripheral nociceptors. These findings highlight the critical role of membrane transporters in regulating the excitability of sensory neurons and provide a cellular mechanism linking monoamine dysregulation, particularly involving the DAT, to enhanced trigeminal nociception and potentially migraine pathogenesis.