Activation of p38 MAPK in the rostral ventromedial medulla by visceral noxious inputs transmitted via the dorsal columns may contribute to pelvic organ cross-sensitization in rats with endometriosis

Chen, Z.; Xie, Fei; Bao, Mengmeng; Li, X.; Chao, Yi‐Ping; Lin, Chi-Chung; Guo, Renhua; Zhang, C.; Wu, Anshi; Yue, Yun; Guan, Yun; Wang, Y.

doi:10.1016/j.neuroscience.2015.02.021

Cited by 23 publications

(20 citation statements)

References 33 publications

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“…This is supported by evidence demonstrating that experimentally induced IBD, cystitis or endometriosis can result in the sensitization of adjacent pelvic organs (for example, intestines, bladder and uterus). 148 , 149 , 150 , 151 A similar phenomenon is observed clinically with the clustering of comorbidities in women with pelvic pain, such as patients with irritable bowel often presenting with viscero-visceral (for example, bladder or menstrual pain) or viscero-somatic (for example, pelvic muscle spasm, temporomandibular pain) complaints.…”

Section: Neuroimmune Contributions To the Female Predominance Of Painmentioning

confidence: 53%

Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain

et al. 2016

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In the central nervous system, bidirectional signaling between glial cells and neurons (‘neuroimmune communication') facilitates the development of persistent pain. Spinal glia can contribute to heightened pain states by a prolonged release of neurokine signals that sensitize adjacent centrally projecting neurons. Although many persistent pain conditions are disproportionately common in females, whether specific neuroimmune mechanisms lead to this increased susceptibility remains unclear. This review summarizes the major known contributions of glia and neuroimmune interactions in pain, which has been determined principally in male rodents and in the context of somatic pain conditions. It is then postulated that studying neuroimmune interactions involved in pain attributed to visceral diseases common to females may offer a more suitable avenue for investigating unique mechanisms involved in female pain. Further, we discuss the potential for primed spinal glia and subsequent neurogenic inflammation as a contributing factor in the development of peripheral inflammation, therefore, representing a predisposing factor for females in developing a high percentage of such persistent pain conditions.

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Section: Neuroimmune Contributions To the Female Predominance Of Painmentioning

confidence: 53%

Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain

et al. 2016

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“…A proportion of women with endometriosis have a neuropathic component involved in their pain mechanism (Whitaker et al ., 2016). Interestingly, an animal model of endometriosis has shown p38 MAPK activation to play a role in this mechanism (Chen et al ., 2015). Chronic pain patients appear less able to engage nociceptive pain processing and to produce endogenous pain inhibition (Tracey and Mantyh, 2007) and recent work suggests that dysfunction within this system may predispose an individual to develop chronic pain after an acute insult (De Felice et al ., 2011).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide genetic analyses highlight mitogen-activated protein kinase (MAPK) signaling in the pathogenesis of endometriosis

et al. 2017

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STUDY QUESTIONDo genome-wide association study (GWAS) data for endometriosis provide insight into novel biological pathways associated with its pathogenesis?SUMMARY ANSWERGWAS analysis uncovered multiple pathways that are statistically enriched for genetic association signals, analysis of Stage A disease highlighted a novel variant in MAP3K4, while top pathways significantly associated with all endometriosis and Stage A disease included several mitogen-activated protein kinase (MAPK)-related pathways.WHAT IS KNOWN ALREADYEndometriosis is a complex disease with an estimated heritability of 50%. To date, GWAS revealed 10 genomic regions associated with endometriosis, explaining <4% of heritability, while half of the heritability is estimated to be due to common risk variants. Pathway analyses combine the evidence of single variants into gene-based measures, leveraging the aggregate effect of variants in genes and uncovering biological pathways involved in disease pathogenesis.STUDY DESIGN, SIZE, DURATIONPathway analysis was conducted utilizing the International Endogene Consortium GWAS data, comprising 3194 surgically confirmed endometriosis cases and 7060 controls of European ancestry with genotype data imputed up to 1000 Genomes Phase three reference panel. GWAS was performed for all endometriosis cases and for Stage A (revised American Fertility Society (rAFS) I/II, n = 1686) and B (rAFS III/IV, n = 1364) cases separately. The identified significant pathways were compared with pathways previously investigated in the literature through candidate association studies.PARTICIPANTS/MATERIALS, SETTING, METHODSThe most comprehensive biological pathway databases, MSigDB (including BioCarta, KEGG, PID, SA, SIG, ST and GO) and PANTHER were utilized to test for enrichment of genetic variants associated with endometriosis. Statistical enrichment analysis was performed using the MAGENTA (Meta-Analysis Gene-set Enrichment of variaNT Associations) software.MAIN RESULTS AND THE ROLE OF CHANCEThe first genome-wide association analysis for Stage A endometriosis revealed a novel locus, rs144240142 (P = 6.45 × 10−8, OR = 1.71, 95% CI = 1.23–2.37), an intronic single-nucleotide polymorphism (SNP) within MAP3K4. This SNP was not associated with Stage B disease (P = 0.086). MAP3K4 was also shown to be differentially expressed in eutopic endometrium between Stage A endometriosis cases and controls (P = 3.8 × 10−4), but not with Stage B disease (P = 0.26). A total of 14 pathways enriched with genetic endometriosis associations were identified (false discovery rate (FDR)-P < 0.05). The pathways associated with any endometriosis were Grb2-Sos provides linkage to MAPK signaling for integrins pathway (P = 2.8 × 10−5, FDR-P = 3.0 × 10−3), Wnt signaling (P = 0.026, FDR-P = 0.026) and p130Cas linkage to MAPK signaling for integrins pathway (P = 6.0 × 10−4, FDR-P = 0.029); with Stage A endometriosis: extracellular signal-regulated kinase (ERK)1 ERK2 MAPK (P = 5.0 × 10−4, FDR-P = 5.0 × 10−4) and with Stage B endometriosis: two overlappin...

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“…15,45,76 Moreover, there is abundant indirect evidence that ON-cells contribute to hyperalgesia in neuropathy, opioid-induced hyperalgesia, and other persistent pain states. 10,14,21,59,62,70,71,73 A better understanding of the interactions between the PB and RVM in conditions of injury and inflammation should therefore provide critical insights into the plasticity of pain-modulation in persistent pain. 11,15,20,61 …”

Section: Discussionmentioning

confidence: 99%

Parabrachial complex links pain transmission to descending pain modulation

Roeder

Chen

Davis

et al. 2016

Pain

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The rostral ventromedial medulla (RVM) has a well-documented role in pain modulation, and exerts anti-nociceptive and pro-nociceptive influences mediated by two distinct classes of neurons, OFF-cells and ON-cells. OFF-cells are defined by a sudden pause in firing in response to nociceptive inputs, whereas ON-cells are characterized by a “burst” of activity. Although these reflex-related changes in ON- and OFF-cell firing are critical to their pain-modulating function, the pathways mediating these responses have not been identified. The present experiments were designed to test the hypothesis that nociceptive input to the RVM is relayed through the parabrachial complex (PB). In electrophysiological studies, ON- and OFF-cells were recorded in the RVM of lightly anesthetized male rats before and after an infusion of lidocaine or muscimol into PB. The ON-cell burst and OFF-cell pause evoked by noxious heat or mechanical probing were substantially attenuated by inactivation of the lateral, but not medial, parabrachial area. Retrograde tracing studies showed that neurons projecting to the RVM were scattered throughout PB. Few of these neurons expressed calcitonin gene-related peptide (CGRP), suggesting that the RVM projection from PB is distinct from that to the amygdala. These data show that a substantial component of “bottom-up” nociceptive drive to RVM pain-modulating neurons is relayed through the parabrachial complex. While the parabrachial complex is well-known as an important relay for ascending nociceptive information, its functional connection with the RVM allows the spinoparabrachial pathway to access descending control systems as part of a recurrent circuit.

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Activation of p38 MAPK in the rostral ventromedial medulla by visceral noxious inputs transmitted via the dorsal columns may contribute to pelvic organ cross-sensitization in rats with endometriosis

Cited by 23 publications

References 33 publications

Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain

Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain

Genome-wide genetic analyses highlight mitogen-activated protein kinase (MAPK) signaling in the pathogenesis of endometriosis

Parabrachial complex links pain transmission to descending pain modulation

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