Role of Toll-like Receptor 4 Signaling in Mast Cell-Mediated Migraine Pain Pathway

Degranulation of meningeal mast cells leading to the sensitization of trigeminal vascular afferent processing is believed to be one of the mechanisms underlying the migraine pain pathway. Recent work suggests that Toll-like receptor 4 (TLR4) may be involved in signaling states of central sensitization. Using a murine model of light aversion produced by compound 48/80 (2 mg/kg, intraperitoneal) mast cell degranulation, employed as a surrogate marker for photophobia observed in migraineurs, we examined the role of TLR4 in migraine-like behavior and neuronal activation. Using a two-chambered light/dark box, we found that compound 48/80 administration in male and female C57Bl/6 mice produced light aversion lasting up to 2 h, and that pre-treatment with sumatriptan (1 mg/kg, i.p.) reliably prevented this effect. Genetic deletion and pharmacological blockade of TLR4 with TAK-242 (3 mg/kg, i.p.) reversed the light aversive effects of compound 48/80 in males but not in females. Assessing the downstream signaling pathway in mutant mice, we found that the TLR4-mediated, light aversion was dependent upon myeloid differentiation primary response gene 88 but not Toll-interleukin-1 receptor domain-containing adapter-inducing interferon-beta signaling. In separate groups, male mice sacrificed at 10 min following compound 48/80 revealed a significant increase in the incidence of evoked p-extracellular signal-regulated kinases (+) neurons in the nucleus caudalis of wild type but not Tlr4(-/-) mice or in mice pre-treated with sumatriptan. This study thus provides the first evidence for involvement of TLR4 signaling through MyD88 in initiating and maintaining migraine-like behavior and nucleus caudalis neuronal activation in the mouse.