Migraine is thought to involve sensitization of the trigeminal nociceptive system. In preclinical pain models, activation of MNK-eIF4E signaling contributes to nociceptor sensitization and the development of persistent pain. Despite these observations, the role of MNK signaling in migraine remains unclear. Here, we investigate whether activation of MNK contributes to hypersensitivity in two rodent models of migraine. Female and male wild-type (WT) and MNK1 knock-out (KO) mice were subjected to repeated restraint stress or a dural injection of interleukin-6 (IL-6) and tested for periorbital hypersensitivity and grimacing. Upon returning to baseline thresholds, stressed mice were administered a low dose of the nitric oxide donor sodium nitroprusside (SNP) and mice previously injected with IL-6 were given a second dural injection of pH 7.0 to test for hyperalgesic priming. MNK1 KO mice were significantly less hypersensitive than WTs following dural IL-6 and did not prime to pH 7.0 or SNP. Furthermore, treatment with the selective MNK inhibitor, eFT508, in WT mice prevented hypersensitivity caused by dural IL-6 or pH 7.0. Together, these results implicate MNK-eIF4E signaling in the development of pain originating from the dura and strongly suggest that targeting MNK inhibition may have significant therapeutic potential as a treatment for migraine.
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