Sensitizing effect of antimigraine drug sumatriptan on capsaicin-sensitive lung vagal neurons via 5-HT_1B/1D receptors and PKA: Relevance to adverse chest effects

Background: The antimigraine drug sumatriptan causes adverse chest effects, namely dyspnea and chest tightness, through unclear mechanisms. Dyspnea is an unpleasant sensation evoked by peripheral sensory signals transmitted to the central nervous system. Capsaicin-sensitive lung vagal (CSLV) afferents are nociceptive-like fibers that provide sensory input from the airways and lungs, mediating airway defense reflexes and evoking unpleasant respiratory sensations. The present study was carried out to investigate the role of CSLV afferents in mediating these adverse chest effects. Methods: Experiments were performed using male Brown-Norway rats. In an in vivo study, we investigated the effect of sumatriptan on CSLV-fiber activities and fiber-mediated airway reflexes using single fiber recordings and breathing pattern monitoring in anesthetized rats. In an in vitro study, the effect of sumatriptan on neuronal sensitivity was evaluated using Ca²⁺ imaging in rat primary cultured CSLV neurons. Results: Our results showed that intravenous infusion of sumatriptan increased the excitability of CSLV afferents to chemical and mechanical stimuli in anesthetized rats; this sensitizing effect occurred 3–20 minutes after termination of the sumatriptan infusion and reversed by 80 minutes later. In isolated CSLV neurons, sumatriptan-induced enhancement of Ca²⁺ transients evoked by capsaicin was blocked by pretreatment with a 5-hydroxytryptamine 1B and 1D (5-HT_1B/1D) receptor antagonist and a protein kinase A inhibitor, whereas an antagonist of the transient receptor potential ankyrin 1 failed to do so. Additionally, in anesthetized, spontaneously breathing rats, a sumatriptan infusion potentiated changes in CSLV afferent-mediated breathing patterns, suggesting that enhanced sensory signals were transmitted to the central nervous system. Similarly, this potentiating effect was also abolished by a 5-HT_1B/1D receptor antagonist. Furthermore, immunofluorescence staining confirmed that 5-HT_1B/1D receptors were expressed in isolated CSLV neurons. Conclusions: We concluded that sumatriptan sensitizes CSLV afferents through a direct action on 5-HT_1B/1D receptors expressing in nerve endings followed by protein kinase A activation in rats. These findings suggest that sensitization of CSLV afferents may contribute to the chest discomfort experienced by some migraineurs following sumatriptan administration.