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A new mechanistic approach for the treatment of chronic neuropathic pain with nitrous oxide integrated from a systems biology narrative review.

ABSTRACT: The limitations of the currently available treatments for chronic neuropathic pain highlight the need for safer and more effective alternatives. The authors carried out a focused review using a systems biology approach to integrate the complex mechanisms of nociception and neuropathic pain, and to decipher the effects of nitrous oxide (N₂O) on those pathways, beyond the known effect of N₂O on N-methyl-D-aspartate receptors. This review identified a number of potential mechanisms by which N₂O could impact the processes involved in peripheral and central sensitization. In the ascending pathway, the effects of N₂O include activating TWIK-related K⁺ channel 1 potassium channels on first-order neurons, blocking voltage-dependent calcium channels to attenuate neuronal excitability, attenuating postsynaptic glutamatergic receptor activation, and possibly blocking voltage-dependent sodium channels. In the descending pathway, N₂O induces the release of endogenous opioid ligands and stimulates norepinephrine release. In addition, N₂O may mediate epigenetic changes by inhibiting methionine synthase, a key enzyme involved in DNA and RNA methylation. This could explain why this short-acting analgesic has shown long-lasting anti-pain sensitization effects in animal models of chronic pain. These new hypotheses support the rationale for investigating N₂O, either alone or in combination with other analgesics, for the management of chronic neuropathic pain.

SUBMITTER: Bessiere B

PROVIDER: S-EPMC8103977 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundChronic neuropathic pain is a condition affecting an increasing proportion of the general population and its management requires a comprehensive, multidisciplinary program. A growing body of evidence supports the use of hyperbaric oxygen therapy (HBOT) in several chronic neuropathic pain conditions; however, its role and efficacy remain unclear.PurposeTo summarize current evidence for the mechanistic rationale of HBOT in chronic neuropathic pain conditions and to evaluate its clinical efficacy.MethodsThis narrative review was conducted after searching the following databases (Medline, Embase, Cochrane, PsycINFO, the Web of Science, Scopus, ClinicalTrials. gov, WHO ICTRP, and ProQuest Digital Dissertation) from January 1946 to March 2020. Articles published in English that involved either animal or human studies with acute or chronic neuropathic pain evaluating any HBOT-related intervention were included.ResultsA total of 2971 citations were identified. A total of 29 studies were included in this review. The mechanisms of action for HBOT use in neuropathic conditions included the primary effects of hyperoxia and edema resolution, as well as the secondary effects pertinent to the production of oxygen and nitrogen reactive species (serving as pain signaling molecules), nitric oxide-dependent release of opioid peptides, and reduction of inflammatory mediators. A robust evidence for HBOT use in the clinical setting was associated with chronic regional pain syndrome and chronic primary bladder pain syndrome. Some evidence supported its use for chronic secondary (peripheral) neuropathic pain including radiation-induced plexus neuropathies, postherpetic neuralgia, and trigeminal neuralgia.ConclusionsHBOT has been shown to have antinociceptive and analgesic effects in animal models of inflammatory, neuropathic, and chronic pain. Human studies demonstrated beneficial effects of HBOT in improving clinical outcomes such as pain scores, pain-related symptoms, and quality of life. A systematic methodology of HBOT application is necessary to confirm its safety and efficacy.

Project description:Preeclampsia is a disease of the mother, fetus, and placenta, and the gaps in our understanding of the complex interactions among their respective disease pathways preclude successful treatment and prevention. The placenta has a key role in the pathogenesis of the terminal pathway characterized by exaggerated maternal systemic inflammation, generalized endothelial damage, hypertension, and proteinuria. This sine qua non of preeclampsia may be triggered by distinct underlying mechanisms that occur at early stages of pregnancy and induce different phenotypes. To gain insights into these molecular pathways, we employed a systems biology approach and integrated different "omics," clinical, placental, and functional data from patients with distinct phenotypes of preeclampsia. First trimester maternal blood proteomics uncovered an altered abundance of proteins of the renin-angiotensin and immune systems, complement, and coagulation cascades in patients with term or preterm preeclampsia. Moreover, first trimester maternal blood from preterm preeclamptic patients in vitro dysregulated trophoblastic gene expression. Placental transcriptomics of women with preterm preeclampsia identified distinct gene modules associated with maternal or fetal disease. Placental "virtual" liquid biopsy showed that the dysregulation of these disease gene modules originates during the first trimester. In vitro experiments on hub transcription factors of these gene modules demonstrated that DNA hypermethylation in the regulatory region of ZNF554 leads to gene down-regulation and impaired trophoblast invasion, while BCL6 and ARNT2 up-regulation sensitizes the trophoblast to ischemia, hallmarks of preterm preeclampsia. In summary, our data suggest that there are distinct maternal and placental disease pathways, and their interaction influences the clinical presentation of preeclampsia. The activation of maternal disease pathways can be detected in all phenotypes of preeclampsia earlier and upstream of placental dysfunction, not only downstream as described before, and distinct placental disease pathways are superimposed on these maternal pathways. This is a paradigm shift, which, in agreement with epidemiological studies, warrants for the central pathologic role of preexisting maternal diseases or perturbed maternal-fetal-placental immune interactions in preeclampsia. The description of these novel pathways in the "molecular phase" of preeclampsia and the identification of their hub molecules may enable timely molecular characterization of patients with distinct preeclampsia phenotypes.

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A new mechanistic approach for the treatment of chronic neuropathic pain with nitrous oxide integrated from a systems biology narrative review.

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