Different immune cells mediate mechanical pain hypersensitivity in male and female mice

Sorge, Robert E.; Mapplebeck, Josiane C.S.; Rosen, Sarah F.; Beggs, Simon; Taves, Sarah; Alexander, Jessica K.; Martin, Loren J.; Austin, Jean-Sébastien; Sotocinal, Susana G.; Chen, Di; Yang, Mu; Shi, Xiang Qun; Huang, Hao; Pillon, Nicolas; Bilan, Philip J.; Tu, YuShan; Klip, Amira; Ji, Ru-Rong; Zhang, Ji; Salter, Michael W.; Mogil, Jeffrey S.

doi:10.1038/nn.4053

Cited by 1,135 publications

(1,238 citation statements)

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“…In a follow-up study, Sorge et al (2015) found equivalent morphologic activation of microglia in the spinal cords of male and female mice in response to peripheral nerve injury, accompanied by similar levels of allodynia. However, spinal inhibition of microglial function with minocycline, P2X4 blocker, or microglial BDNF signaling or by elimination of spinal microglia with a toxin reduced mechanical allodynia in male but not female mice.…”

Section: Introductionmentioning

confidence: 91%

Microglial Signaling in Chronic Pain with a Special Focus on Caspase 6, p38 MAP Kinase, and Sex Dependence

et al. 2016

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Microglia are the resident immune cells in the spinal cord and brain. Mounting evidence suggests that activation of microglia plays an important role in the pathogenesis of chronic pain, including chronic orofacial pain. In particular, microglia contribute to the transition from acute pain to chronic pain, as inhibition of microglial signaling reduces pathologic pain after inflammation, nerve injury, and cancer but not baseline pain. As compared with inflammation, nerve injury induces much more robust morphologic activation of microglia, termed microgliosis, as shown by increased expression of microglial markers, such as CD11b and IBA1. However, microglial signaling inhibitors effectively reduce inflammatory pain and neuropathic pain, arguing against the importance of morphologic activation of microglia in chronic pain sensitization. Importantly, microglia enhance pain states via secretion of proinflammatory and pronociceptive mediators, such as tumor necrosis factor α, interleukins 1β and 18, and brain-derived growth factor. Mechanistically, these mediators have been shown to enhance excitatory synaptic transmission and suppress inhibitory synaptic transmission in the pain circuits. While early studies suggested a predominant role of microglia in the induction of chronic pain, further studies have supported a role of microglia in the maintenance of chronic pain. Intriguingly, recent studies show male-dominant microglial signaling in some neuropathic pain and inflammatory pain states, although both sexes show identical morphologic activation of microglia after nerve injury. In this critical review, we provide evidence to show that caspase 6—a secreted protease that is expressed in primary afferent axonal terminals surrounding microglia—is a robust activator of microglia and induces profound release of tumor necrosis factor α from microglia via activation of p38 MAP kinase. The authors also show that microglial caspase 6/p38 signaling is male dominant in some inflammatory and neuropathic pain conditions. Finally, the authors discuss the relevance of microglial signaling in chronic trigeminal and orofacial pain.

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Section: Introductionmentioning

confidence: 91%

Microglial Signaling in Chronic Pain with a Special Focus on Caspase 6, p38 MAP Kinase, and Sex Dependence

et al. 2016

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“…More recent are surprising reports of marked sex differences in signal transduction pathways in hippocampal circuits that also seem to represent a case of 'convergence' such that the same physiological problem (state) is solved differently in each sex [60]. Divergent pathways to cell death [61,62] and sexually dimorphic cellular origins of pain [63] are additional startling examples. These latter examples demonstrate convergence rather than compensation as it is not clear what one sex is lacking versus the other, but we may not have yet discovered the missing piece.…”

Section: (C) Compensation and Convergence In Sexually Dimorphic Behavmentioning

confidence: 99%

Multifaceted origins of sex differences in the brain

McCarthy

2016

Phil. Trans. R. Soc. B

150

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Studies of sex differences in the brain range from reductionistic cell and molecular analyses in animal models to functional imaging in awake human subjects, with many other levels in between. Interpretations and conclusions about the importance of particular differences often vary with differing levels of analyses and can lead to discord and dissent. In the past two decades, the range of neurobiological, psychological and psychiatric endpoints found to differ between males and females has expanded beyond reproduction into every aspect of the healthy and diseased brain, and thereby demands our attention. A greater understanding of all aspects of neural functioning will only be achieved by incorporating sex as a biological variable. The goal of this review is to highlight the current state of the art of the discipline of sex differences research with an emphasis on the brain and to contextualize the articles appearing in the accompanying special issue.

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“…Most of these studies were performed in male mice. Recently, Sorge et al have demonstrated that nerve injury-induced pain in male mice not in female mice are mediated via TLR4 possibly via microglial activation [46], but via T-lymphocytes instead of microglial cells in female mice [47]. Though the PiSCES report from extensive multicenter human study on sickle pain found no signiicant diference in pain sensation and intensity according to gender diferences [48], it is yet to be demonstrated/veriied whether sickle pain is mediated via gender-speciic pathways.…”

Section: Mechanisms Of Pain In Sickle Cellmentioning

confidence: 99%

Mechanisms of Pain in Sickle Cell Disease

Aich¹,

Beitz²,

Gupta³

2016

Sickle Cell Disease - Pain and Common Chronic Complications

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Pain is one of the most common features of sickle cell disease SCD lacking efective therapy. Pain in SCD is relatively more complicated than other conditions associated with pain requiring understanding of the pathobiology of pain speciic to SCD. The characterization of pain to deine the diverse modalities of nociception in SCD is currently under progress via human studies accompanied by transgenic mouse models of SCD. Sickle pathobiology characterized by oxidative stress, inlammation and vascular dysfunction contributes to both peripheral and central nociceptive sensitization via mast cell activation in the periphery, and reactive oxygen species and glial activation and endoplasmic reticulum stress in the spinal cord among other efectors. These efects are mediated via several cellular receptors, which can be targeted to produce positive therapeutic outcomes. In this chapter, we will discuss the present understanding of molecular mechanisms of SCD pain and outline the mechanism-based translational potential of novel actionable targets to treat SCD pain.Keywords: pain, sickle cell disease, neurogenic inlammation, substance P, mast cell . IntroductionPain is a hallmark feature of sickle cell disease SCD , which can start in infancy, leading to hospitalization, reduced survival and poor quality of life. Pain in SCD is unique because of unpredictable and recurrent episodes of acute pain due to vaso-occlusive crises VOC , in addition to chronic pain experienced by a majority of adult patients on a daily basis [1]. Treatment choices remain limited to opioids, which impose liabilities of their own including constipation, mast cell activation, fear of addiction and respiratory depression [2]. Moreover, signiicantly larger doses of opioids are required to treat pain in SCD as compared to other acute and chronic pain conditions [1]. Pain can be lifelong in SCD and may therefore inluence © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.cognitive function and lead to depression and anxiety, which can in turn promote the perception of pain [1].Treatment of chronic pain remains unsatisfactory overall, perhaps due to the diverse pathobiology in diferent diseases. Therefore, it is critical to understand the mechanisms speciic to the genesis of sickle pain to develop targeted therapies. Vascular dysfunction, inlammation, ischemia/reperfusion injury and oxidative stress in the wake of VOC can each evoke activation of the nociceptive nerve ibers leading to acute pain. On the other hand, con...

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Different immune cells mediate mechanical pain hypersensitivity in male and female mice

Cited by 1,135 publications

References 27 publications

Microglial Signaling in Chronic Pain with a Special Focus on Caspase 6, p38 MAP Kinase, and Sex Dependence

Microglial Signaling in Chronic Pain with a Special Focus on Caspase 6, p38 MAP Kinase, and Sex Dependence

Multifaceted origins of sex differences in the brain

Mechanisms of Pain in Sickle Cell Disease

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