Background: Microglia activation contributes to chronic pain and to the adverse effects of opiate use such as analgesic tolerance and opioid-induced hyperalgesia. Both mu opioid receptor (MOR) encoded by Oprm1/OPRM1 gene and toll like receptor 4 (TLR4) have been reported to mediate these morphine effects and a current question is whether microglia express the Oprm1 transcript and MOR protein. The aim of this study was to characterize Oprm1-MOR expression in naive murine and human microglia, combining transcriptomics datasets previously published by other groups with our own imaging study using the Cx3cr1-eGFP-MOR-mCherry reporter mouse line.Methods: We analyzed microglial Oprm1/OPRM1 expression obtained from transcriptomics datasets, focusing on ex vivo studies from adult wild-type animals and adult post-mortem human cerebral cortex. Oprm1, as well as co-regulated gene sets were examined. The expression of MOR in microglia was also investigated using our novel fluorescent Cx3cr1-eGFP-MOR-mcherry reporter mouse line. We determined whether CX3cR1-eGFP positive microglial cells expressed MOR-mCherry protein by imaging various brain areas including the Frontal Cortex, Nucleus Accumbens, Ventral Tegmental Area, Central Amygdala, and Periaqueductal Gray matter, as well as spinal cord.Results: Oprm1 expression was found in all 12 microglia datasets from mouse whole brain, in 7 out of 8 from cerebral cortex, 3 out of 4 from hippocampus, 1 out of 1 from striatum, and 4 out of 5 from mouse or rat spinal cord. OPRM1 was expressed in 16 out of 17 microglia transcriptomes from human cerebral cortex. In Cx3cr1-eGFP-MOR-mCherry mice, the percentage of MOR-positive microglial cells ranged between 35.4 and 51.6% in the different brain areas, and between 36.8 and 42.4% in the spinal cord.Conclusion: The comparative analysis of the microglia transcriptomes indicates that Oprm1/OPRM1 transcripts are expressed in microglia. The investigation of Cx3cr1-eGFP-MOR-mCherry mice also shows microglial expression of MOR proteinin the brain and spine. These results corroborate functional studies showing the actions of MOR agonists on microglia and suppression of these effects by MOR-selective antagonists or MOR knockdown.
A major challenge in medicine is developing potent pain therapies without the adverse effects of opiates. Neuroinflammation and in particular microglial activation have been shown to contribute to these effects. However, the implication of the microglial mu opioid receptor (MOR) is not known. We developed a novel conditional knockout (cKO) mouse line, wherein MOR is deleted in microglia. Morphine analgesic tolerance was delayed in both sexes in cKO mice in the hot plate assay. Opioid-induced hyperalgesia (OIH) as measured in the tail immersion assay was abolished in male cKO mice, and physical dependence to morphine as assessed by naloxone-induced withdrawal was attenuated in female cKO mice. Our results show a sex-dependent contribution of microglial MOR in morphine analgesic tolerance, OIH, and physical dependence.In conclusion, our data suggest that blockade of microglial MOR could represent a therapeutic target for opiate analgesia without the opiate adverse effects.
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are neuropeptides with wide, complementary, and overlapping distributions in the central and peripheral nervous systems, where they exert important regulatory roles in many physiological processes. VIP and PACAP display a large range of biological cellular targets and functions in the adult nervous system including regulation of neurotransmission and neuroendocrine secretion and neuroprotective and neuroimmune responses. As the main focus of the present review, VIP and PACAP also have been long implicated in nervous system development and maturation through their interaction with the seven transmembrane domain G protein-coupled receptors, PAC1, VPAC1, and VPAC2, initiating multiple signaling pathways. Compared with PAC1, which solely binds PACAP with very high affinity, VPACs exhibit high affinities for both VIP and PACAP but differ from each other because of their pharmacological profile for both natural accessory peptides and synthetic or chimeric molecules, with agonistic and antagonistic properties. Complementary to initial pharmacological studies, transgenic animals lacking these neuropeptides or their receptors have been used to further characterize the neuroanatomical, electrophysiological, and behavioral roles of PACAP and VIP in the developing central nervous system. In this review, we recapitulate the critical steps and processes guiding/driving neurodevelopment in vertebrates and superimposing the potential contribution of PACAP and VIP receptors on the given timeline. We also describe how alterations in VIP/PACAP signaling may contribute to both (neuro)developmental and adult pathologies and suggest that tuning of VIP/PACAP signaling in a spatiotemporal manner may represent a novel avenue for preventive therapies of neurological and psychiatric disorders. © 2016 Wiley Periodicals, Inc.
BackgroundLithium is widely used to treat bipolar disorders and displays mood stabilizing properties. In addition, lithium relieves painful cluster headaches and has a strong analgesic effect in neuropathic pain rat models.ObjectivesTo investigate the analgesic effect of lithium on the cuff model of neuropathic pain.MethodsWe used behavioral and pharmacological approaches to study the analgesic effect of a single injection of lithium in wild-type and mu opioid receptor (MOR) null cuffed neuropathic mice. Mass spectrometry and enzyme-linked immunosorbent assay allowed to measure the levels of endogenous MOR agonist beta-endorphin as well as monoamines in brain and plasma samples 4 h after lithium administration.ResultsA single injection of lithium chloride (100 mg/kg, ip) alleviated mechanical allodynia for 24 h, and this effect was absent in MOR null neuropathic mice. Biochemical analyses highlight a significant increase in beta-endorphin levels by 30% in the brain of lithium-treated mice compared to controls. No variation of beta-endorphin was detected in the blood.ConclusionsTogether, our results provide evidence that lithium induces a long-lasting analgesia in neuropathic mice presumably through elevated brain levels of beta-endorphin and the activation of MORs.
Our data suggests that tolerance to the analgesic effects of morphine is not linked to increased glucuronidation to M3G or to altered global BBB permeability of morphine.
On 8 June 2020, we, a diverse group of African emerging researchers, published a response to the commentary titled 'Why are black South African students less likely to consider studying biological sciences?' (1) published in the South Africa Journal of Science (SAJS). There are mounting arguments, in both print and social media, regarding the merits of the Nattrass (2020) commentary, particularly around its strong racial undertones as well as poor and unethical research practices. Nattrass' commentary has been intensely divisive, managing to engender stereotypes, anger, and disappointment. Conflicting arguments have emerged, which involve responses by other academics, politicians, and the public, but much of the furore has been strongly biased towards and along racial lines, with very little attention directed at the flawed nature of the research. Such questions as the one asked by Nattrass (1) in the title of the commentary are valid and should be explored. Such research, in fact any research, must involve scientific rigour, robust methodological approaches, sensitivity and adherence to ethical principles. With the right approach and the involvement of multi-sector collaborators, we can begin to innovatively and constructively address the potential societal challenges that may arise. Science should be respected and trusted, and should build a fundamental basis for societal benefits and decision-making processes. Issues of race, whether socially constructed or not (2) are sensitive, and should be treated as such. When dealing with sensitive subjects, it is important to be cognizant of one's inherent unconscious biases. To drive this, scientists, editors, leaders in academia and industry, government research institutions, NGOs and publishers have taken steps to promote ethical conduct in research by signing The Singapore Statement on Research Integrity (3). The Statement was founded on four principles: viz. honesty, accountability, professionalism, and stewardship, which inform the fourteen responsibilities of ethical research conduct. As researchers, it is important that we use these principles and responsibilities to guide our research, and to maintain our responsibilities to each other, to the people and to the environment. For this reason, we wish to express our concern that the Nattrass (2020) commentary and the research contained therein, has violated many of these governing principles. Moreover, in publishing this commentary with all its methodological flaws and ethical problems, the South African Journal of Science (SAJS) has also violated these principles and responsibilities.
Background: Tamoxifen is used to treat breast cancer and cancer recurrences. After administration, tamoxifen is converted into two more potent antitumor compounds, 4OH-tamoxifen and endoxifen by the CYP3A4/5 and 2D6 enzymes in human. These active compounds are inactivated by the same UDP-glucuronosyltransferase isoforms as those involved in the metabolism of morphine. Importantly, cancer-associated pain can be treated with morphine, and the common metabolic pathway of morphine and tamoxifen suggests potential clinically relevant interactions. Methods: Mouse liver microsomes were used to determine the impact of morphine on 4OH-tamoxifen metabolism in vitro. For in vivo experiments, female mice were first injected with tamoxifen alone and then with tamoxifen and morphine. Blood was collected, and LC-MS/MS was used to quantify tamoxifen, 4OH-tamoxifen, N-desmethyltamoxifen, endoxifen, 4OH-tamoxifen-glucuronide, and endoxifen-glucuronide. Results: In vitro, we found increased K m values for the production of 4OH-tamoxifen-glucuronide in the presence of morphine, suggesting an inhibitory effect on 4OH-tamoxifen glucuronidation. Conversely, in vivo morphine treatment decreased 4OH-tamoxifen levels in the blood while dramatically increasing the formation of inactive metabolites 4OH-tamoxifen-glucuronide and endoxifen-glucuronide. Conclusions: Our findings emphasize the need for caution when extrapolating results from in vitro metabolic assays to in vivo drug metabolism interactions. Importantly, morphine strongly impacts tamoxifen metabolism in mice. It suggests that tamoxifen efficiency could be reduced when both drugs are co-administered in a clinical setting, e.g., to relieve pain in breast cancer patients. Further studies are needed to assess the potential for tamoxifen-morphine metabolic interactions in humans.
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