Hypoxic ventilatory response in Tac1−/− neonatal mice following exposure to opioids

2012 ◽  
Vol 113 (11) ◽  
pp. 1718-1726 ◽  
Author(s):  
J. Berner ◽  
Y. Shvarev ◽  
A. Zimmer ◽  
R. Wickstrom
Keyword(s):  
Substance P ◽  
Intermittent Hypoxia ◽  
Ventilatory Response ◽  
Gene Knockout ◽  
Minute Ventilation ◽  
Neurokinin A ◽  
Hypoxic Ventilatory Response ◽  
Wild Type

Morphine is the dominating analgetic drug used in neonates, but opioid-induced respiratory depression limits its therapeutic use. In this study, we examined acute morphine effects on respiration during intermittent hypoxia in newborn Tac1 gene knockout mice (Tac1−/−) lacking substance P and neurokinin A. In vivo, plethysmography revealed a blunted hypoxic ventilatory response (HVR) in Tac1−/− mice. Morphine (10 mg/kg) depressed the HVR in wild-type animals through an effect on respiratory frequency, whereas it increased tidal volumes in Tac1−/− during hypoxia, resulting in increased minute ventilation. Apneas were reduced during the first hypoxic episode in both morphine-exposed groups, but were restored subsequently in Tac1−/− mice. Morphine did not affect ventilation or apnea prevalence during baseline conditions. In vitro, morphine (50 nM) had no impact on anoxic response of brain stem preparations of either strain. In contrast, it suppressed the inspiratory rhythm during normoxia and potentiated development of posthypoxic neuronal arrest, especially in Tac1−/−. Thus this phenotype has a higher sensitivity to the depressive effects of morphine on inspiratory rhythm generation, but morphine does not modify the reactivity to oxygen deprivation. In conclusion, although Tac1−/− mice are similar to wild-type animals during normoxia, they differed by displaying a reversed pattern with an improved HVR during intermittent hypoxia both in vivo and in vitro. These data suggest that opioids and the substance P-ergic system interact in the HVR, and that reducing the activity in the tachykinin system may alter the respiratory effects of opioid treatment in newborns.

scholarly journals On the existence of a central respiratory oxygen sensor

2017 ◽  
Vol 123 (5) ◽  
pp. 1344-1349 ◽  
Author(s):  
Alexander V. Gourine ◽  
Gregory D. Funk
Keyword(s):  
Experimental Evidence ◽  
Oxygen Sensor ◽  
Ventilatory Response ◽  
Lung Ventilation ◽  
Partial Recovery ◽  
Hypoxic Ventilatory Response ◽  
Peripheral Chemoreceptor ◽  
Terrestrial Mammals

A commonly held view that dominates both the scientific and educational literature is that in terrestrial mammals the central nervous system lacks a physiological hypoxia sensor capable of triggering increases in lung ventilation in response to decreases in Po2 of the brain parenchyma. Indeed, a normocapnic hypoxic ventilatory response has never been observed in humans following bilateral resection of the carotid bodies. In contrast, almost complete or partial recovery of the hypoxic ventilatory response after denervation/removal of the peripheral respiratory oxygen chemoreceptors has been demonstrated in many experimental animals when assessed in an awake state. In this essay we review the experimental evidence obtained using in vitro and in vivo animal models, results of human studies, and discuss potential mechanisms underlying the effects of CNS hypoxia on breathing. We consider experimental limitations and discuss potential reasons why the recovery of the hypoxic ventilatory response has not been observed in humans. We review recent experimental evidence suggesting that the lower brain stem contains functional oxygen sensitive elements capable of stimulating respiratory activity independently of peripheral chemoreceptor input.

scholarly journals miR-203 Regulates Nociceptive Sensitization after Incision by Controlling Phospholipase A2 Activating Protein Expression

2012 ◽  
Vol 117 (3) ◽  
pp. 626-638 ◽  
Author(s):  
Yuan Sun ◽  
Xiang-Qi Li ◽  
Peyman Sahbaie ◽  
Xiao-You Shi ◽  
Wen-Wu Li ◽  
...  
Keyword(s):  
Substance P ◽  
Phospholipase A2 ◽  
Mechanical Allodynia ◽  
Gene Knockout ◽  
Skin Inflammation ◽  
Local Effect ◽  
Intraplantar Injection ◽  
Gene Knockout Mice

Background After incision keratinocytes in the epidermis become activated to produce a range of pain-related mediators. microRNA 203 (miR-203) is known to be involved in keratinocyte growth, differentiation, and skin inflammation. We hypothesized that one or more of these mediators might be under the control of miR-203. Methods The expression of miR-203 and its target gene, phospholipase A2 activating protein (PLAA), were examined after hind paw incision in mice. We investigated the local effect of intraplantar PLAA peptide injection in normal mice and the effects of a selective secretory phospholipase A2 inhibitor (HK064) on PLAA or incision-induced mechanical allodynia. Last, we investigated the role of substance P signaling in regulating miR-203 and PLAA expression in vitro and in vivo. Results Levels of miR-203 were strongly down-regulated in keratinocytes after incision. Informatics-based approaches identified PLAA as a likely candidate for regulation by miR-203. PLAA caused mechanical allodynia and conditioned place aversion but not thermal sensitization. HK064 reduced mechanical allodynia after incision and after intraplantar injection of PLAA. Using preprotachykinin gene knockout mice or with neurokinin-1 selective antagonist LY303870 treatment, we observed that substance P-mediated signaling was also required for miR-203 and PLAA regulation after incision. Finally, using the rat epidermal keratinocyte cell line, we observed that a miR-203 mimic molecule could block the substance P-induced increase in PLAA expression observed under control conditions. Conclusions miR-203 may regulate expression of the novel nociceptive mediator PLAA after incision. Furthermore, the regulation of miR-203 and PLAA levels is reliant upon intact substance P signaling.

scholarly journals Contractile effects of substance P and neurokinin A on the rat stomach in vivo and in vitro

1987 ◽  
Vol 90 (1) ◽  
pp. 273-279 ◽  
Author(s):  
Ulrike Holzer-Petsche ◽  
Fred Lembeck ◽  
Helmut Seitz
Keyword(s):  
Substance P ◽  
Neurokinin A ◽  
Rat Stomach

scholarly journals Gestational stress delays maturation of the hypoxic ventilatory response: an in vivo and in vitro study

2009 ◽  
Vol 23 (S1) ◽  
Author(s):  
Richard Kinkead ◽  
Stéphanie Fournier ◽  
Sébastien Fournier ◽  
Nicolas Voituron ◽  
Gérard Hilaire
Keyword(s):  
Ventilatory Response ◽  
In Vitro Study ◽  
Vitro Study ◽  
Hypoxic Ventilatory Response ◽  
Gestational Stress

scholarly journals Effects of ANG II on bradykinin receptor gene expression in cardiomyocytes and vascular smooth muscle cells

2001 ◽  
Vol 281 (4) ◽  
pp. H1778-H1783 ◽  
Author(s):  
Ekaterina Kintsurashvili ◽  
Irena Duka ◽  
Irene Gavras ◽  
Conrado Johns ◽  
Dimitrios Farmakiotis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Knockout ◽  
Receptor Gene ◽  
Ang Ii ◽  
Wild Type ◽  
Receptor Mrna ◽  
Gene Knockout Mice ◽  
Receptor Gene Expression

Bradykinin has vasodilatory and tissue-protective effects exerted via its B2 type receptor, whereas the B1 receptor is constitutively absent but inducible by inflammation and toxins. In previous studies, we found that B2 receptor gene knockout mice exhibit overexpression of the B1 receptor, which assumes a vasodilatory function and is further upgraded in renovascular hypertension. The present study was designed to explore the effects of excess angiotensin II (ANG II) on B1 receptor and B2 receptor gene expression in mouse cardiomyocytes and rat vascular smooth muscle cells (VSMC) in vivo (after a 3-day infusion of 30 ng/min ANG II in 11 wild-type and in 13 genetically engineered mice with deleted B2 receptor gene) and in vitro (ANG II added in rat VSMC culture in the presence or absence of AT1 or AT2 receptor antagonist). Expression of B1 and B2 receptor mRNA was assessed by reverse transcriptase-polymerase chain reaction. ANG II infusion caused upregulation by 30% of the already significantly overexpressed B1 receptors in cardiomyocytes of the B2receptor gene knockout mice, but in the wild-type mice it upregulated only the B2 receptor mRNA by 47%. The addition of ANG II in VSMC culture produced a time-dependent induction of B1and upregulation of B2 receptor gene expression, maximal at 3 h (by fivefold), declining almost to baseline by 24 h. The addition of losartan completely blocked this effect, whereas the AT2 blocker PD-123319 made no difference, indicating that this is an AT1-mediated effect of ANG II. The data indicate that excess ANG II in subpressor doses in vivo upregulates expression of the B2 receptor, but in its absence, the already overexpressed B1 receptor is further upregulated, evidently assuming a counterregulatory response; in vitro, it transiently upregulates both bradykinin receptors.

scholarly journals Interleukin-10 Is a Natural Suppressor of Cytokine Production and Inflammation in a Murine Model of Allergic Bronchopulmonary Aspergillosis

1997 ◽  
Vol 185 (6) ◽  
pp. 1089-1100 ◽  
Author(s):  
Gabriele Grünig ◽  
David B. Corry ◽  
Michael W. Leach ◽  
Brian W.P. Seymour ◽  
Viswanath P. Kurup ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Gene Knockout ◽  
Allergic Bronchopulmonary Aspergillosis ◽  
Interleukin 10 ◽  
Lung Cells ◽  
Wild Type ◽  
Outbred Mice ◽  
Ifn Γ

We have used interleukin-10 (IL-10) gene knockout mice (IL-10−/−) to examine the role of endogenous IL-10 in allergic lung responses to Aspergillus fumigatus Ag. In vitro restimulated lung cells from sensitized IL-10−/− mice produced exaggerated amounts of IL-4, IL-5, and interferon-γ (IFN-γ) compared with wild-type (WT) lung cells. In vivo, the significance of IL-10 in regulating responses to repeated A. fumigatus inhalation was strikingly revealed in IL-10−/− outbred mice that had a 50–60% mortality rate, while mortality was rare in similarly treated WT mice. Furthermore, IL-10−/− outbred mice exhibited exaggerated airway inflammation and heightened levels of IL-5 and IFN-γ in bronchoalveolar lavage (BAL) fluids. In contrast, the magnitude of the allergic lung response was similar in intranasally (i.n.) sensitized IL-10−/− and wild-type mice from a different strain (C57BL/6). Using a different route of priming (intraperitoneal) followed by one i.n. challenge we found that IL-10−/− C57BL/6 mice had heightened eosinophilic airway inflammation, BAL–IL-5 levels, and numbers of αβT cells in the lung tissues compared with WT mice. We conclude that IL-10 can suppress inflammatory Th2-like lung responses as well as Th1-like responses given the constraints of genetic background and route of priming.

Altered respiratory pattern and hypoxic response in transgenic newborn mice lacking the tachykinin-1 gene

2007 ◽  
Vol 103 (2) ◽  
pp. 552-559 ◽  
Author(s):  
J. Berner ◽  
Y. Shvarev ◽  
H. Lagercrantz ◽  
A. Bilkei-Gorzo ◽  
T. Hökfelt ◽  
...  
Keyword(s):  
Substance P ◽  
Transgenic Mice ◽  
Respiratory Rhythm ◽  
Respiratory Pattern ◽  
Whole Body ◽  
Neurokinin A ◽  
Newborn Mice ◽  
Early Maturation

Substance P is known to be involved in respiratory rhythm and central pattern-generating mechanisms, especially during early development. We therefore studied respiratory responses in transgenic newborn mice (Tac1−/−) lacking substance P and neurokinin A (NKA). In vivo, the effects of intermittent isocapnic hypoxia (IH) and hypercapnia were studied using whole body flow plethysmography at P2-3 and P8-10. In vitro, anoxic responses and the effects of hypocapnic and hypercapnic conditions were studied in brain stem-spinal cord preparations (C4 activity) at P2. Hypoxic challenge considerably modified the respiratory activity in transgenic mice displayed in vivo as an attenuated increase in tidal volume during IH. Transgenic mice also showed a more prominent posthypoxic frequency decline in vivo, and posthypoxic neuronal arrests appeared more often in vitro. We recognized two types of sigh activity: with or without a following pause. During IH, the amount of sighs with a pause decreased and those without increased, a redistribution that became stronger with age only in controls. Intermittent anoxia induced long-term facilitation effects in controls, but not in Tac1−/− animals, manifested as an increase in burst frequency in vitro and by an augmentation of ventilation during posthypoxic periods in vivo. Thus our data demonstrate that a functional substance P/NKA system is of great importance for the generation of an adequate respiratory response to hypoxic provocation in newborn mice and during early maturation. It also indicates that substance P (and/or NKA) is involved in the development of the plasticity of the respiratory system.

Targeted deletion of the neutral endopeptidase gene alters ventilatory responses to acute hypoxia in mice

1999 ◽  
Vol 87 (4) ◽  
pp. 1266-1271 ◽  
Author(s):  
H. Grasemann ◽  
B. Lu ◽  
A. Jiao ◽  
J. Boudreau ◽  
N. P. Gerard ◽  
...  
Keyword(s):  
Substance P ◽  
Carotid Body ◽  
Genetic Background ◽  
Ventilatory Response ◽  
Acute Hypoxia ◽  
Neutral Endopeptidase ◽  
Hypoxic Ventilatory Response ◽  
Wild Type ◽  
Targeted Deletion ◽  
Ventilatory Responses

Neutral endopeptidase (NEP) is one of the major endopeptidases responsible for the inactivation of substance P in the carotid body, a neurotransmitter shown to be important in the transduction of hypoxic stimuli. Ventilatory responses to acute hypoxia were measured by indirect plethysmography in unanesthetized, unrestrained wild-type mice and in mice in which the NEP gene was deleted (NEP -/-). Ventilation was measured while the animals breathed room air: 12% O2 in N2 and 8% O2 in N2. Deletion of the NEP gene caused marked alterations in both the magnitude and composition of the hypoxic ventilatory response to both 8% O2 in N2 and 12% O2 in N2, compared with the wild-type mice (C57BL/6J) on the same genetic background as the NEP -/- mice. Treatment of C57BL/6J mice with thiorphan, a NEP inhibitor, resulted in a greater ventilatory response to 8% O2 because of a significantly greater shortening of expiratory time. The results of these studies demonstrate that NEP plays an important role in modifying the expression of the ventilatory response to acute hypoxia.

scholarly journals Arabidopsis Disulfide Reductase, Trx-h2, Functions as an RNA Chaperone under Cold Stress

2021 ◽  
Vol 11 (15) ◽  
pp. 6865
Author(s):  
Eun Seon Lee ◽  
Joung Hun Park ◽  
Seong Dong Wi ◽  
Ho Byoung Chae ◽  
Seol Ki Paeng ◽  
...  
Keyword(s):  
Cold Stress ◽  
Wild Type ◽  
Rna Chaperone ◽  
E Coli ◽  
Cold Sensitive ◽  
Thioredoxin H ◽  
Functional Rnas

The thioredoxin-h (Trx-h) family of Arabidopsis thaliana comprises cytosolic disulfide reductases. However, the physiological function of Trx-h2, which contains an additional 19 amino acids at its N-terminus, remains unclear. In this study, we investigated the molecular function of Trx-h2 both in vitro and in vivo and found that Arabidopsis Trx-h2 overexpression (Trx-h2OE) lines showed significantly longer roots than wild-type plants under cold stress. Therefore, we further investigated the role of Trx-h2 under cold stress. Our results revealed that Trx-h2 functions as an RNA chaperone by melting misfolded and non-functional RNAs, and by facilitating their correct folding into active forms with native conformation. We showed that Trx-h2 binds to and efficiently melts nucleic acids (ssDNA, dsDNA, and RNA), and facilitates the export of mRNAs from the nucleus to the cytoplasm under cold stress. Moreover, overexpression of Trx-h2 increased the survival rate of the cold-sensitive E. coli BX04 cells under low temperature. Thus, our data show that Trx-h2 performs function as an RNA chaperone under cold stress, thus increasing plant cold tolerance.

scholarly journals Neuroprotective Potential of a Small Molecule RET Agonist in Cultured Dopamine Neurons and Hemiparkinsonian Rats

2021 ◽  
pp. 1-24
Author(s):  
Juho-Matti Renko ◽  
Arun Kumar Mahato ◽  
Tanel Visnapuu ◽  
Konsta Valkonen ◽  
Mati Karelson ◽  
...  
Keyword(s):  
Mapk Signaling ◽  
Dopamine Neurons ◽  
Dopamine Depletion ◽  
Wild Type ◽  
Disease Modifying Therapy ◽  
Immortalized Cells ◽  
Midbrain Dopamine ◽  
6 Hydroxydopamine

Background: Parkinson’s disease (PD) is a progressive neurological disorder where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor symptoms. Currently, no treatment is able to halt the progression of PD. Glial cell line-derived neurotrophic factor (GDNF) rescues degenerating dopamine neurons both in vitro and in animal models of PD. When tested in PD patients, however, the outcomes from intracranial GDNF infusion paradigms have been inconclusive, mainly due to poor pharmacokinetic properties. Objective: We have developed drug-like small molecules, named BT compounds that activate signaling through GDNF’s receptor, the transmembrane receptor tyrosine kinase RET, both in vitro and in vivo and are able to penetrate through the blood-brain barrier. Here we evaluated the properties of BT44, a second generation RET agonist, in immortalized cells, dopamine neurons and rat 6-hydroxydopamine model of PD. Methods: We used biochemical, immunohistochemical and behavioral methods to evaluate the effects of BT44 on dopamine system in vitro and in vivo. Results: BT44 selectively activated RET and intracellular pro-survival AKT and MAPK signaling pathways in immortalized cells. In primary midbrain dopamine neurons cultured in serum-deprived conditions, BT44 promoted the survival of the neurons derived from wild-type, but not from RET knockout mice. BT44 also protected cultured wild-type dopamine neurons from MPP +-induced toxicity. In a rat 6-hydroxydopamine model of PD, BT44 reduced motor imbalance and could have protected dopaminergic fibers in the striatum. Conclusion: BT44 holds potential for further development into a novel, possibly disease-modifying therapy for PD.

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