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

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          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.

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          Most cited references43

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          Pathological pain and the neuroimmune interface.

          Reciprocal signalling between immunocompetent cells in the central nervous system (CNS) has emerged as a key phenomenon underpinning pathological and chronic pain mechanisms. Neuronal excitability can be powerfully enhanced both by classical neurotransmitters derived from neurons, and by immune mediators released from CNS-resident microglia and astrocytes, and from infiltrating cells such as T cells. In this Review, we discuss the current understanding of the contribution of central immune mechanisms to pathological pain, and how the heterogeneous immune functions of different cells in the CNS could be harnessed to develop new therapeutics for pain control. Given the prevalence of chronic pain and the incomplete efficacy of current drugs--which focus on suppressing aberrant neuronal activity--new strategies to manipulate neuroimmune pain transmission hold considerable promise.
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            Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model.

            Although the trigeminal nerve innervates the meninges and participates in the genesis of migraine headaches, triggering mechanisms remain controversial and poorly understood. Here we establish a link between migraine aura and headache by demonstrating that cortical spreading depression, implicated in migraine visual aura, activates trigeminovascular afferents and evokes a series of cortical meningeal and brainstem events consistent with the development of headache. Cortical spreading depression caused long-lasting blood-flow enhancement selectively within the middle meningeal artery dependent upon trigeminal and parasympathetic activation, and plasma protein leakage within the dura mater in part by a neurokinin-1-receptor mechanism. Our findings provide a neural mechanism by which extracerebral cephalic blood flow couples to brain events; this mechanism explains vasodilation during headache and links intense neurometabolic brain activity with the transmission of headache pain by the trigeminal nerve.
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              Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice.

              The innate immune system is increasingly appreciated to play an important role in the mediation of chronic pain, and one molecule implicated in this process is the Toll-like receptor 4 (TLR4). Here, using pharmacological and genetic manipulations, we found that activating TLR4 in the spinal cord, with the agonist lipopolysaccharide (LPS), causes robust mechanical allodynia but only in male mice. Spinal LPS had no pain-producing effect in female mice. TLR4 also has a sex-specific role in inflammatory (complete Freund's adjuvant) and neuropathic (spared nerve injury) pain: pain behaviors were TLR4 dependent in males but TLR4 independent in females. The sex differences appear to be specific to the spinal cord, as LPS administered to the brain or the hindpaw produces equivalent allodynia in both sexes, and specific to pain, as intrathecal LPS produces equivalent hypothermia in both sexes. The involvement of TLR4 in pain behaviors in male mice is dependent on testosterone, as shown by gonadectomy and hormone replacement. We found no sex differences in spinal Tlr4 gene expression at baseline or after LPS, suggesting the existence of parallel spinal pain-processing circuitry in female mice not involving TLR4.
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                Author and article information

                Journal
                Mol Pain
                Mol Pain
                MPX
                spmpx
                Molecular Pain
                SAGE Publications (Sage CA: Los Angeles, CA )
                1744-8069
                08 August 2019
                2019
                : 15
                : 1744806919867842
                Affiliations
                [1 ]Department of Anesthesiology, University of California San Diego, La Jolla CA, USA
                [2 ]Department of Dermatology, University of California San Diego, La Jolla, CA, USA
                [3 ]Division of Rheumatology, Allergy, and Immunology, University of California San Diego, La Jolla, CA, USA
                [4 ]Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
                Author notes
                [*]Roshni Ramachandran, Department of Anesthesiology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 0818, USA. Email: rushileo@ 123456gmail.com
                Author information
                https://orcid.org/0000-0003-4508-5135
                Article
                10.1177_1744806919867842
                10.1177/1744806919867842
                6688145
                31342858
                f699ef38-8f48-475b-a679-55cd48142a13
                © The Author(s) 2019

                Creative Commons CC BY: This article is distributed under the terms of the Creative Commons Attribution 4.0 License ( http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 19 September 2018
                : 9 May 2019
                : 4 June 2019
                Funding
                Funded by: Migraine Research Foundation, FundRef http://doi.org/10.13039/100003965;
                Categories
                Research Article
                Custom metadata
                January-December 2019

                Molecular medicine
                migraine,tlr4,mast cell,compound 48/80,myd88
                Molecular medicine
                migraine, tlr4, mast cell, compound 48/80, myd88

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