Sex differences in μ‐opioid receptor expression in trigeminal ganglia under a myositis condition in rats

Zhang, X.; Zhang, Y.; Asgar, Jamila; Niu, Katelyn Y.; Lee, J.; Lee, K.S.; Schneider, Markus; Ro, Jin Y.

doi:10.1002/j.1532-2149.2013.00352.x

Cited by 40 publications

(43 citation statements)

References 67 publications

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“…All mice were housed in groups of 3-5, separated based on sex and litter, maintained on a 12-hour light / 12-hour dark cycle, and given ad libitum access to food and water in a temperature-controlled room. Estrous phase was not measured in order to prevent heightened stress in female mice [23,37]. All procedures were approved by Nanjing University of Chinese Medicine Animal Care and Use Committee.…”

Section: Animalsmentioning

confidence: 99%

“…Previous studies investigating sex differences of μ opioid agonist analgesia were always focusing on the expression of μ opioid receptor (probably only a matter of MOR1) in Periaqueducatal Gray (PAG) by ethology, pharmacology, neuroanatomy, immunohistochemistry and immunofluorescence [6,23,30,36,37]. Aiming to demonstrate the relationship between OPRM1 splice variant and sex differences and using the established RT-SYBR green qPCR assays, we examined the expression levels of OPRM1 splice variants mRNA in six brain regions and spinal cord of male and female C57BL/6 Mice.…”

Section: Expression Levels Of Oprm1 Splice Variants Mrna In Brain Regmentioning

confidence: 99%

“…It has been demonstrated that sex differences in the effects of peripheral MOR agonists is partly mediated by sex differences in the changes of MOR expressions [34], tolerance/dependence results from different adaptational strategies (chronic systemic morphine influenced levels of MOR splice variant mRNA) in males and females [35], MOR expression in the PAG was sexually dimorphic contributed to the observed sex differences in morphine potency [36] and testosterone plays a key role in the regulation of MOR under inflammatory conditions and these differences in the antihyperalgesic effects of peripherally administered opioids are mediated by peripheral opioid receptor expression levels partially [37]. Thus, we determined to explore the different effects of μ opioid receptor agonists and aimed to investigate the mRNA expression of MOR variants of different brain regions by SYBR green quantitative PCR (qPCR) in male and female mice and prepared to figure out some certain relationships between MOR variants and these sex-associated reactions.…”

Section: Introductionmentioning

confidence: 99%

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Sex Associated Differential Expressions of the Alternatively Spliced Variants mRNA of OPRM1 in Brain Regions of C57BL/6 Mouse

Liu

Zhang

Qin

et al. 2018

Cell Physiol Biochem

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Background/Aims: Opiates are potent analgesics but their clinical use is limited by sex-associated side effects, such as drug tolerance, opioid-induced hyperalgesia and withdrawal reaction. OPRM1, as the main receptor of opioids, plays an important role in the pharmacological process of opioids in rodents and human. We have previously investigated OPRM1, the μ opioid receptor gene, which have dozens of alternatively spliced variants probably correlating with opioid-induced effects in brain regions of four inbred mouse strains and demonstrated the strain-specific expressions of these splice variants. Also, within a strain, the regional expression patterns of some of the variants were similar while others were opposite. Thus, we are aiming to seek out the relationship between sex differences and these alternatively spliced variants. Methods: The present studies follow a SYBR green quantitative PCR (qPCR) which we had used before to examine the expression of OPRM1 splice variant mRNAs in selected brain regions of male and female C57BL/6 mice. Sex-associated differences in baseline latency, opioid-induced tolerance, analgesia and addiction were examined and determined by Tail-flick test, jumps and statistical analysis. Results: The mRNA levels of opioid receptor gene splice variants in male and female mice showed significant differences among the brain regions, implying region-specific alternative splicing of the OPRM1 gene, which was consistent with our previous study. More importantly, the complete mRNA expression profiles of the OPRM1 splice variants was also gender-specific, suggesting a sexual influence on OPRM1 alternative splicing. Conclusion: In brief, we put forward that the distinctions among baseline latency, opioid-induced tolerance, analgesia and physical dependence in male and female mice might correlate with sex associated differential expressions of OPRM1 gene.

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Section: Animalsmentioning

confidence: 99%

Section: Expression Levels Of Oprm1 Splice Variants Mrna In Brain Regmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sex Associated Differential Expressions of the Alternatively Spliced Variants mRNA of OPRM1 in Brain Regions of C57BL/6 Mouse

Liu

Zhang

Qin

et al. 2018

Cell Physiol Biochem

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“…Neuronal MOR tone is also modified by increased glial activity, such that the release of proinflammatory cytokines upregulates MOR expression in males but not females (Zhang et al 2014). Increased release of pro-nociceptive messengers from glia, sex differences in anti-inflammatory EM2 activity, and a lack of MOR upregulation upon glial cell activation may further contribute to the attenuated response to morphine observed in females.…”

Section: Current Hypotheses Underlying Sex Differences In Morphine Anmentioning

confidence: 99%

Sex differences in innate immunity and its impact on opioid pharmacology

Doyle

Murphy

2016

J of Neuroscience Research

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Morphine has been and continues to be one of the most potent and widely used drugs for the treatment of pain. Clinical and animal models investigating sex differences in pain and analgesia demonstrate that morphine is a more potent analgesic in males than in females. In addition to binding to the neuronal mu opioid receptor, morphine binds to the innate immune receptor toll-like receptor 4 (TLR4), located on glial cells. Activation of glial TLR4 initiates a neuroinflammatory response that directly opposes morphine analgesia. Females of many species have a more active immune system than males; however, few studies have investigated glial cells as a potential mechanism driving sexually dimorphic responses to morphine. This review illustrates the involvement of glial cells in key processes underlying observed sex differences in morphine analgesia, and suggests that targeting glia may improve current treatment strategies for pain.

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“…A few studies report the involvement of testosterone in pain, inflammation and analgesia, (Claiborne et al, 2006; Fischer et al, 2007; Nag and Mokha, 2009; Torres-Chavez et al, 2012) and mechanisms underlying testosterone-mediated sexually dimorphic responses under pathological pain conditions have been proposed (Sorge et al, 2011; Niu et al, 2012; Zhang et al, 2014). In most studies that investigated the role of testosterone in pain and analgesia, it is assumed that testosterone effects are mediated by AR.…”

Section: Introductionmentioning

confidence: 99%

Androgen receptor transcriptionally regulates μ-opioid receptor expression in rat trigeminal ganglia

et al. 2016

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The involvement of testosterone in pain, inflammation, and analgesia has been reported, but the role of androgen receptor (AR), a steroid receptor for testosterone, is not well understood. We have previously shown that peripheral inflammation upregulates μ-opioid receptor (MOR) in rat trigeminal ganglia (TG) in a testosterone-dependent manner. In this study, we hypothesized that testosterone regulates MOR expression via transcriptional activities of AR in TG. We first examined whether AR is co-expressed with MOR in TG neurons. Our immunohistochemical experiment revealed that AR staining is detected in neurons of all sizes in TG and that a subset of AR is expressed in MOR as well as in TRPV1-positive neurons. We identified the promoter region of the rat MOR gene contains putative AR binding sites. Using chromatin immunoprecipitation assay, we demonstrated that AR directly binds to these sites in TG extracts. We confirmed with luciferase reporter assay that AR activated the MOR promoter in response to androgens in a human neuroblastoma cell line (5H-5YSY). These data demonstrated that AR functions as a transcriptional regulator of the MOR gene activity. Finally, we showed that flutamide, a specific AR antagonist, prevents complete Freund’s adjuvant (CFA)-induced upregulation of MOR mRNA in TG, and that flutamide dose-dependently blocks the efficacy of DAMGO, a specific MOR agonist, on CFA-induced mechanical hypersensitivity. Our results expand the knowledge regarding the role of androgens and their receptor in pain and analgesia and have important clinical implications, particularly for inflammatory pain patients with low or compromised plasma testosterone levels.

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Sex differences in μ‐opioid receptor expression in trigeminal ganglia under a myositis condition in rats

Cited by 40 publications

References 67 publications

Sex Associated Differential Expressions of the Alternatively Spliced Variants mRNA of OPRM1 in Brain Regions of C57BL/6 Mouse

Sex Associated Differential Expressions of the Alternatively Spliced Variants mRNA of OPRM1 in Brain Regions of C57BL/6 Mouse

Sex differences in innate immunity and its impact on opioid pharmacology

Androgen receptor transcriptionally regulates μ-opioid receptor expression in rat trigeminal ganglia

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