scholarly journals Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

2017 ◽  
Vol 114 (31) ◽  
pp. 8396-8401 ◽  
Author(s):  
Miguel A. Tejada ◽  
Angeles Montilla-García ◽  
Shane J. Cronin ◽  
Domagoj Cikes ◽  
Cristina Sánchez-Fernández ◽  
...  
Keyword(s):  
Immune Cells ◽  
Thermal Hyperalgesia ◽  
Opioid Analgesia ◽  
Endogenous Opioid ◽  
Drug Induced ◽  
Immune Infiltrate ◽  
Pathophysiological Role ◽  
Sigma 1 ◽  
Peripheral Opioid Analgesia

Sigma-1 antagonism potentiates the antinociceptive effects of opioid drugs, so sigma-1 receptors constitute a biological brake to opioid drug-induced analgesia. The pathophysiological role of this process is unknown. We aimed to investigate whether sigma-1 antagonism reduces inflammatory pain through the disinhibition of the endogenous opioidergic system in mice. The selective sigma-1 antagonists BD-1063 and S1RA abolished mechanical and thermal hyperalgesia in mice with carrageenan-induced acute (3 h) inflammation. Sigma-1–mediated antihyperalgesia was reversed by the opioid antagonists naloxone and naloxone methiodide (a peripherally restricted naloxone analog) and by local administration at the inflamed site of monoclonal antibody 3-E7, which recognizes the pan-opioid sequence Tyr–Gly–Gly–Phe at the N terminus of most endogenous opioid peptides (EOPs). Neutrophils expressed pro-opiomelanocortin, the precursor of β-endorphin (a known EOP), and constituted the majority of the acute immune infiltrate. β-endorphin levels increased in the inflamed paw, and this increase and the antihyperalgesic effects of sigma-1 antagonism were abolished by reducing the neutrophil load with in vivo administration of an anti-Ly6G antibody. The opioid-dependent sigma-1 antihyperalgesic effects were preserved 5 d after carrageenan administration, where macrophages/monocytes were found to express pro-opiomelanocortin and to now constitute the majority of the immune infiltrate. These results suggest that immune cells harboring EOPs are needed for the antihyperalgesic effects of sigma-1 antagonism during inflammation. In conclusion, sigma-1 receptors curtail immune-driven peripheral opioid analgesia, and sigma-1 antagonism produces local opioid analgesia by enhancing the action of EOPs of immune origin, maximizing the analgesic potential of immune cells that naturally accumulate in painful inflamed areas.

Acetaminophen Responsive miR-19b Modulates SIRT1/Nrf2 Signaling Pathway in Drug-Induced Hepatotoxicity

2019 ◽  
Vol 170 (2) ◽  
pp. 476-488 ◽  
Author(s):  
Xing Liu ◽  
Hongqian Zhao ◽  
Chunyan Luo ◽  
Debin Du ◽  
Jinlong Huang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Antioxidant Defense ◽  
Compensatory Mechanism ◽  
Drug Induced ◽  
Antioxidant Genes ◽  
Sirt1 Expression ◽  
Nrf2 Signaling Pathway ◽  
Pathophysiological Role

AbstractPrevious studies suggest that activation of SIRT1 protects liver from acetaminophen (APAP)-induced injury; however, the detailed mechanism of SIRT1 modulation in this process is still incomplete. Therefore, this study was to investigate the pathophysiological role of SIRT1 in APAP-mediated hepatotoxicity. We found that SIRT1 mRNA and protein were markedly upregulated in human LO2 cells and mouse liver upon APAP exposure. In vitro, the specific knockdown of SIRT1 expression ultimately aggravated APAP-evoked cellular antioxidant defense in LO2 cells. Moreover, lentivirus-mediated knockdown of hepatic SIRT1 expression exacerbated APAP-induced oxidative stress and liver injury, especially reduction of Nrf2 and subsequent downregulation of several antioxidant genes. Intriguingly, 30 mg/kg SRT1720, the specific SIRT1 activator, which greatly enhanced Nrf2 expression and antioxidant defense, and then eventually reversed APAP-induced hepatic liver injury in mice. Furthermore, APAP responsive miR-19b played an important role in regulating SIRT1 expression, whereas overexpression miR-19b largely abolished the induction of SIRT1 by APAP in vitro and in vivo. Specific SIRT1 3′-UTR mutation, which disrupted the interaction of miRNA-3′UTR, and successfully abrogated the modulation by miR-19b. Notably, hepatic miR-19b overexpression worsened the APAP-induced hepatotoxicity. In general, our results support the notion that the strong elevation of SIRT1 by APAP responsive miR-19b may represent a compensatory mechanism to protect liver against the drug-induced damage, at least in part by enhancing Nrf2-mediated antioxidant capacity in the liver.

Endogenous opioids mediate stress-induced analgesia

2018 ◽  
Author(s):  
Claudia Sommer
Keyword(s):  
Opioid Receptors ◽  
Immune Cells ◽  
Endogenous Opioids ◽  
Sensory Nerves ◽  
Opioid Analgesia ◽  
Endogenous Opioid Peptides ◽  
Endogenous Opioid ◽  
First Time ◽  
Endogenous Analgesia

This chapter reviews the landmark paper published in 1990 by Stein et al. and entitled ‘Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation’. Opioids, besides acting centrally as analgesics, may act peripherally upon opioid receptors located on axons and on immune cells. In the publication by Stein et al., it was shown for the first time that endogenous opioid peptides released from immune cells mediate stress-induced analgesia, potentially through opioid receptors on peripheral nerve endings. This finding has led to numerous follow-up studies on endogenous analgesia, including work showing that cannabinoid analgesia is mediated via the peripheral release of opioids, and to the concept of topical opioid analgesia, which may be a good way of using the potent analgesia that opioids can convey, without their CNS-associated side effects.

Modulation of Peripheral Endogenous Opioid Analgesia by Central Afferent Blockade

2003 ◽  
Vol 98 (1) ◽  
pp. 195-202 ◽  
Author(s):  
Thomas K. Schmitt ◽  
Shaaban A. Mousa ◽  
Alexander Brack ◽  
Diego K. Schmidt ◽  
Heike L. Rittner ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Cells ◽  
Cold Water ◽  
Intrathecal Morphine ◽  
Opioid Analgesia ◽  
Endogenous Opioid ◽  
Freund’S Complete Adjuvant ◽  
Freund's Complete Adjuvant ◽  
Pressure Threshold ◽  
Endogenous Analgesia

Background Peripheral tissue injury causes a migration of opioid peptide-containing immune cells to the inflamed site. The subsequent release and action of these peptides on opioid receptors localized on peripheral sensory nerve terminals causes endogenous analgesia. The spinal application of opioid drugs blocks the transmission of nociceptive information from peripheral injury. This study investigates the influence of exogenous spinal opioid analgesia on peripheral endogenous opioid analgesia. Methods Six and forty-eight hours after initiation of continuous intrathecal morphine infusion and administration of Freund's complete adjuvant into the hind paw of rats, antinociceptive and antiinflammatory effects were measured by paw pressure threshold, paw volume, and paw temperature, respectively. Inflammation and quantity of opioid-containing cells were evaluated by immunocytochemistry and flow cytometry. Cold water swim stress-induced endogenous analgesia was examined 24 h after discontinuation of intrathecal morphine administration. Results Intrathecal morphine (10 micro g/h) resulted in a significant and stable increase of paw pressure threshold ( P< 0.05) without changing inflammation, as evaluated by paw volume, paw temperature, and flow cytometry ( P> 0.05). At 48 but not at 6 h after Freund's complete adjuvant, the number of beta-endorphin-containing cells and cold water swim-induced antinociception were significantly reduced in intrathecal morphine-treated rats compared with those treated with intrathecal vehicle ( P< 0.05). Conclusions These findings suggest an interplay of central and peripheral mechanisms of pain control. An effective central inhibition of pain apparently signals a reduced need for recruitment of opioid-containing immune cells to injured sites.

[123I]TPCNE: A novel SPET tracer for the sigma-1 receptor binds irreversibly in humans in vivo

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S655-S655
Author(s):  
James M Stone ◽  
Erik Arstad ◽  
Kjell Erlandsson ◽  
Rikki N Waterhouse ◽  
Peter J Ell ◽  
...  
Keyword(s):  
Sigma 1 Receptor ◽  
Sigma 1

Increased Circulatory Extrarenal 1α,25-Dihydroxyvitamin D3 in Bilaterally Nephrectomized Rats

2020 ◽  
Vol 20 (9) ◽  
pp. 1523-1530
Author(s):  
Murat Dabak ◽  
Durrin O. Dabak ◽  
Tuncay Kuloglu ◽  
Ersoy Baydar ◽  
Hakan Bulut ◽  
...  
Keyword(s):  
Immune Cells ◽  
Low Dose ◽  
Systemic Circulation ◽  
Bilateral Nephrectomy ◽  
Dihydroxyvitamin D3 ◽  
Hydroxyvitamin D ◽  
Inflammatory Conditions ◽  
Calcium Phosphorus ◽  
25 Hydroxyvitamin D

Background: Extrarenal 1α,25-dihydroxyvitamin D3 (1,25-D) locally produced by immune cells plays crucial roles in the regulation of the immune system. However, in vivo status of extrarenal 1,25-D and 25-hydroxyvitamin D (25-D) in acute inflammatory conditions are unknown. Objective: The aim of this study was to determine the extrarenal 1,25-D level in circulation in bilaterally nephrectomized rats, induced by low-dose lipopolysaccharide (LPS). Methods: Renal 1,25-D synthesis was terminated through bilateral nephrectomy in rats. The rats received intraperitoneal LPS (50 μg/kg BW) three times and the experiment was ended 24 hours after nephrectomy. Serum 1,25-D, 25-D, calcium, phosphorus, intact parathyroid hormone, and calcitonin levels were measured and immunohistochemistry was applied to detect the sources of extrarenal 1,25- D synthesis. Results: Circulatory 1,25-D concentration remarkably increased in both LPS-treated and non-treated bilaterally nephrectomized rats. Elevated circulatory 1,25-D did not have hypercalcemic endocrinal effects. The increased 1,25-D level also resulted in a concurrent rapid and dramatic depletion of circulatory 25-D. Conclusions: Extrarenal 1,25-D could enter into the systemic circulation and, therefore, might have systemic effects besides its autocrine and paracrine functions.

scholarly journals Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3through CYP3A4 induction in vitro and in vivo: Implications for drug-induced osteomalacia

2013 ◽  
Vol 28 (5) ◽  
pp. 1101-1116 ◽  
Author(s):  
Zhican Wang ◽  
Yvonne S Lin ◽  
Leslie J Dickmann ◽  
Emma-Jane Poulton ◽  
David L Eaton ◽  
...  
Keyword(s):  
Drug Induced ◽  
Cyp3a4 Induction

scholarly journals A human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aubin Michalon ◽  
Andreas Hagenbuch ◽  
Christian Huy ◽  
Evita Varela ◽  
Benoit Combaluzier ◽  
...  
Keyword(s):  
Immune Cells ◽  
Ex Vivo ◽  
Phase 1 ◽  
Hereditary Disease ◽  
Elderly Subjects ◽  
Human Antibody ◽  
Cardiac Amyloid ◽  
Healthy Elderly ◽  
Ongoing Phase

AbstractTransthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive analyses of memory B cell repertoires derived from healthy elderly subjects. NI301A binds selectively with high affinity to the disease-associated ATTR aggregates of either wild-type or variant ATTR related to sporadic or hereditary disease, respectively. It does not bind physiological transthyretin. NI301A removes ATTR deposits ex vivo from patient-derived myocardium by macrophages, as well as in vivo from mice grafted with patient-derived ATTR fibrils in a dose- and time-dependent fashion. The biological activity of ATTR removal involves antibody-mediated activation of phagocytic immune cells including macrophages. These data support the evaluation of safety and tolerability of NI301A in an ongoing phase 1 clinical trial in patients with ATTR cardiomyopathy.

scholarly journals FOXE1-Dependent Regulation of Macrophage Chemotaxis by Thyroid Cells In Vitro and In Vivo

2021 ◽  
Vol 22 (14) ◽  
pp. 7666
Author(s):  
Sara C. Credendino ◽  
Marta De Menna ◽  
Irene Cantone ◽  
Carmen Moccia ◽  
Matteo Esposito ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Immune Cells ◽  
Cancer Susceptibility ◽  
Macrophage Infiltration ◽  
M2 Macrophage ◽  
Thyroid Cells ◽  
Transcriptional Alterations ◽  
Cancer Phenotypes

Forkhead box E1 (FOXE1) is a lineage-restricted transcription factor involved in thyroid cancer susceptibility. Cancer-associated polymorphisms map in regulatory regions, thus affecting the extent of gene expression. We have recently shown that genetic reduction of FOXE1 dosage modifies multiple thyroid cancer phenotypes. To identify relevant effectors playing roles in thyroid cancer development, here we analyse FOXE1-induced transcriptional alterations in thyroid cells that do not express endogenous FOXE1. Expression of FOXE1 elicits cell migration, while transcriptome analysis reveals that several immune cells-related categories are highly enriched in differentially expressed genes, including several upregulated chemokines involved in macrophage recruitment. Accordingly, FOXE1-expressing cells induce chemotaxis of co-cultured monocytes. We then asked if FOXE1 was able to regulate macrophage infiltration in thyroid cancers in vivo by using a mouse model of cancer, either wild type or with only one functional FOXE1 allele. Expression of the same set of chemokines directly correlates with FOXE1 dosage, and pro-tumourigenic M2 macrophage infiltration is decreased in tumours with reduced FOXE1. These data establish a novel link between FOXE1 and macrophages recruitment in the thyroid cancer microenvironment, highlighting an unsuspected function of this gene in the crosstalk between neoplastic and immune cells that shape tumour development and progression.

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