Tryptophan deficiency reduces the effectiveness of sumatriptan in a mouse model of migraine
Résumé
Objective: Triptans are a specific acute treatment for migraine attacks by activating serotonin (5-HT) 1B/1D receptors (5-HTR1B/1D). However, approximately 30% of patients with migraine do not respond to it or only partially. The mechanisms of this inefficacy are unclear. Tryptophan (Trp), 5-HT precursor, has been involved in migraine pathophysiology and can modulate the 5-HTR expression. Thus, we studied the contribution of Trp on sumatriptan efficacy in a preclinical model of migraine. Methods: Adult female C57BL/6 mice were subjected to a Trp-deficient diet for one week before migrainelike pain induction by an acute injection of isosorbide dinitrate (ISDN i.p.). Behavioral cephalic mechanical sensitivity and light sensitivity, cFos-immunoreactivity (IR) in the trigeminal nucleus caudalis (Sp5C), plasma protein extravasation (PPE) and 5-HTR1B/1D expression in the trigeminal ganglion (TG) and Sp5c were evaluated. Results: Trp-deficient diet reduced circulating Trp and 5-HT concentrations by 70% and 13% respectively. In control mice, Trp deficiency had no effect on the baseline cutaneous or light sensitivities, but induced cFos-IR in the Sp5C and PPE in the brain. Additionally, Trp-deficient diet worsened ISDN-induced cephalic mechanical hypersensitivity without impacting ISDN induced light hypersensitivity or cFos-IR. Interestingly, Trp deficiency also blocked the antalgic effect of an acute injection of sumatriptan (1 mg/kg i.p.) on both cutaneous and light hypersensitivities. Finally, Trp deficient mice treated with ISDN exhibited increased 5-HTR1D expression in the TG and the Sp5C, without any changes in 5-HTR1B levels. Conclusion: These findings highlight the critical role of Trp in modulating the sensory response and in regulating the effectiveness of migraine treatments like sumatriptan.