Role of Toll-like receptor 4 signaling in mast cell-mediated migraine pain pathway

Abstract

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-β 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.

Lipid rafts in glial cells: role in neuroinflammation and pain processing

“…First, we and others observed that spinal TLR4 signaling has little effect upon the acute pain state (as after a brief application of a high-intensity thermal stimulus or a mechanical compression), but appears to mediate development of the persistent pain phenotype secondary to local inflammation and to peripheral nerve injury (6)(7)(8)(9)(10)(11)(12)(13). This transition of pain from an acute, stimulus-linked condition to a chronic state has been shown to be a surprisingly common event in both animals and humans (14).…”

Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders

“…The authors suggested that the kynurenine metabolites of l -Trp detected downstream of TLR activation may be an IBS marker. Interestingly, Ramachandrian et al observed that TLR4 signaling was important in initiating and maintaining migraine-like behavior and nucleus caudalis neuronal activation through myeloid differentiation primary response gene 88 (MyD88) in the mouse [ 120 ]. Earlier it was suggested that the 4 896 A > G polymorphism of the TLR -4 gene might be a risk factor for migraine [ 121 ].…”

Toll-Like Receptor Signaling Pathways: Novel Therapeutic Targets for Cerebrovascular Disorders

“…There is growing evidence of the implication of TLRs in various neurodegenerative disorders [ 59 , 60 ], including Alzheimer’s disease [ 61 , 62 , 63 ], Huntington’s disease [ 64 , 65 ], Parkinson’s disease [ 66 ], dementia [ 67 ], and amyotrophic lateral sclerosis [ 68 , 69 ]. Furthermore, TLRs implicated in demyelinating diseases, like multiple sclerosis [ 70 , 71 ] and optic neuritis [ 72 ] and acute neurological disorders, such as epilepsy [ 73 ] and migraine headache [ 74 ], as well as in CNS infections [ 75 ], and traumatic brain injury [ 76 ]. Moreover, TLRs play a role in the modulation of cognitive processes, including learning and memory, and are involved in the pathobiology of psychological disorders, such as anxiety [ 77 ], schizophrenia [ 78 , 79 ], depression [ 80 ].…”