Publications by authors named "Walter J May"

16 Publications

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D-Cysteine Ethyl Ester Reverses the Deleterious Effects of Morphine on Breathing and Arterial Blood-Gas Chemistry in Freely-Moving Rats.

Front Pharmacol 2022 23;13:883329. Epub 2022 Jun 23.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United States.

Cell-penetrant thiol esters including the disulfides, D-cystine diethyl ester and D-cystine dimethyl ester, and the monosulfide, L-glutathione ethyl ester, prevent and/or reverse the deleterious effects of opioids, such as morphine and fentanyl, on breathing and gas exchange within the lungs of unanesthetized/unrestrained rats without diminishing the antinociceptive or sedative effects of opioids. We describe here the effects of the monosulfide thiol ester, D-cysteine ethyl ester (D-CYSee), on intravenous morphine-induced changes in ventilatory parameters, arterial blood-gas chemistry, alveolar-arterial (A-a) gradient (i.e., index of gas exchange in the lungs), and sedation and antinociception in freely-moving rats. The bolus injection of morphine (10 mg/kg, IV) elicited deleterious effects on breathing, including depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive. Subsequent injections of D-CYSee (2 × 500 μmol/kg, IV, given 15 min apart) elicited an immediate and sustained reversal of these effects of morphine. Morphine (10 mg/kg, IV) also A-a gradient, which caused a mismatch in ventilation perfusion within the lungs, and elicited pronounced changes in arterial blood-gas chemistry, including pronounced decreases in arterial blood pH, pO and sO, and equally pronounced increases in pCO (all responses indicative of decreased ventilatory drive). These deleterious effects of morphine were immediately reversed by the injection of a single dose of D-CYSee (500 μmol/kg, IV). Importantly, the sedation and antinociception elicited by morphine (10 mg/kg, IV) were minimally affected by D-CYSee (500 μmol/kg, IV). In contrast, none of the effects of morphine were affected by administration of the parent thiol, D-cysteine (1 or 2 doses of 500 μmol/kg, IV). Taken together, these data suggest that D-CYSee may exert its beneficial effects via entry into cells that mediate the deleterious effects of opioids on breathing and gas exchange. Whether D-CYSee acts as a respiratory stimulant or counteracts the inhibitory actions of µ-opioid receptor activation remains to be determined. In conclusion, D-CYSee and related thiol esters may have clinical potential for the reversal of the adverse effects of opioids on breathing and gas exchange, while largely sparing antinociception and sedation.
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http://dx.doi.org/10.3389/fphar.2022.883329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9260251PMC
June 2022

L-NAC reverses of the adverse effects of fentanyl infusion on ventilation and blood-gas chemistry.

Biomed Pharmacother 2022 Jun 17;153:113277. Epub 2022 Jun 17.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address:

There is an urgent need for development of drugs that are able to reverse the adverse effects of opioids on breathing and arterial blood-gas (ABG) chemistry while preserving opioid analgesia. The present study describes the effects of bolus injections of N-acetyl-L-cysteine (L-NAC, 500 μmol/kg, IV) on ventilatory parameters, ABG chemistry, Alveolar-arterial (A-a) gradient, sedation (righting reflex) and analgesia status (tail-flick latency assay) in unanesthetized adult male Sprague Dawley rats receiving a continuous infusion of fentanyl (1 μg/kg/min, IV). Fentanyl infusion elicited pronounced disturbances in (1) ventilatory parameters (e.g., decreases in frequency of breathing, tidal volume and minute ventilation), (2) ABG chemistry (decreases in pH, pO, sO with increases in pCO), (3) A-a gradient (increases that were consistent with reduced alveolar gas exchange), and (4) sedation and analgesia. Bolus injections of L-NAC given 60 and 90 min after start of fentanyl infusion elicited rapid and sustained reversal of the deleterious effects of fentanyl infusion on ventilatory parameters and ABG chemistry, whereas they did not affect the sedative or analgesic effects of fentanyl. Systemic L-NAC is approved for human use, and thus our findings raise the possibility that this biologically active thiol may be an effective compound to combat opioid-induced respiratory depression in human subjects.
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http://dx.doi.org/10.1016/j.biopha.2022.113277DOI Listing
June 2022

Nitrosyl factors play a vital role in the ventilatory depressant effects of fentanyl in unanesthetized rats.

Biomed Pharmacother 2022 Feb 22;146:112571. Epub 2021 Dec 22.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address:

There is an urgent need to understand the intracellular mechanisms by which synthetic opioids, such as fentanyl, depress breathing. We used L-NAME (N-nitro-L-arginine methyl ester), a nitric oxide synthase (NOS) inhibitor, to provide evidence for a role of nitric oxide (NO) and nitrosyl factors, including S-nitrosothiols, in fentanyl-induced suppression of breathing in rats. We measured breathing parameters using unrestrained plethysmography to record the changes produced by bolus administration of fentanyl (25 μg/kg, IV) in male Sprague Dawley rats that were pretreated with vehicle (saline), L-NAME (50 μmol/kg, IV) or the inactive D-isomer, D-NAME (50 μmol/kg, IV), 15 min previously. L-NAME produced a series of ventilatory changes that included (i) sustained elevations in breathing frequency, due to the reductions in the durations of inspiration and expiration, (ii) sustained elevations in minute ventilation, accompanied by minimal changes in tidal volume, and (iii) increases in inspiratory drive and expiratory drive, and peak inspiratory flow and peak expiratory flow. Subsequent administration of fentanyl in rats pretreated with vehicle produced negative effects on breathing, including decreases in frequency, tidal volume and therefore minute ventilation. Fentanyl elicited markedly different responses in rats that were pretreated with L-NAME, and conclusively, the negative effects of fentanyl were augmented by the NOS inhibitor. D-NAME did not alter ventilatory parameters or modulate the effects of fentanyl on breathing. Our study fully characterized the effects of L-NAME on ventilation in rats and is the first to suggest a potential role of nitrosyl factors in the ventilatory responses to fentanyl. Our data shows that nitrosyl factors reduce the expression of fentanyl-induced changes in ventilation.
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http://dx.doi.org/10.1016/j.biopha.2021.112571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8776621PMC
February 2022

Ventilatory responses during and following hypercapnic gas challenge are impaired in male but not female endothelial NOS knock-out mice.

Sci Rep 2021 10 18;11(1):20557. Epub 2021 Oct 18.

Department of Pediatrics, Case Western Reserve University, Biomedical Research Building BRB 319, 10900 Euclid Avenue Mail Stop 1714, Cleveland, OH, 44106-1714, USA.

The roles of endothelial nitric oxide synthase (eNOS) in the ventilatory responses during and after a hypercapnic gas challenge (HCC, 5% CO, 21% O, 74% N) were assessed in freely-moving female and male wild-type (WT) C57BL6 mice and eNOS knock-out (eNOS-/-) mice of C57BL6 background using whole body plethysmography. HCC elicited an array of ventilatory responses that were similar in male and female WT mice, such as increases in breathing frequency (with falls in inspiratory and expiratory times), and increases in tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives. eNOS-/- male mice had smaller increases in minute ventilation, peak inspiratory flow and inspiratory drive, and smaller decreases in inspiratory time than WT males. Ventilatory responses in female eNOS-/- mice were similar to those in female WT mice. The ventilatory excitatory phase upon return to room-air was similar in both male and female WT mice. However, the post-HCC increases in frequency of breathing (with decreases in inspiratory times), and increases in tidal volume, minute ventilation, inspiratory drive (i.e., tidal volume/inspiratory time) and expiratory drive (i.e., tidal volume/expiratory time), and peak inspiratory and expiratory flows in male eNOS-/- mice were smaller than in male WT mice. In contrast, the post-HCC responses in female eNOS-/- mice were equal to those of the female WT mice. These findings provide the first evidence that the loss of eNOS affects the ventilatory responses during and after HCC in male C57BL6 mice, whereas female C57BL6 mice can compensate for the loss of eNOS, at least in respect to triggering ventilatory responses to HCC.
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http://dx.doi.org/10.1038/s41598-021-99922-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523677PMC
October 2021

Short-term facilitation of breathing upon cessation of hypoxic challenge is impaired in male but not female endothelial NOS knock-out mice.

Sci Rep 2021 09 15;11(1):18346. Epub 2021 Sep 15.

Department of Pediatrics, Biomedical Research Building BRB 319, Case Western Reserve University, 10900 Euclid Avenue Mail Stop 1714, Cleveland, OH, 44106-1714, USA.

Decreases in arterial blood oxygen stimulate increases in minute ventilation via activation of peripheral and central respiratory structures. This study evaluates the role of endothelial nitric oxide synthase (eNOS) in the expression of the ventilatory responses during and following a hypoxic gas challenge (HXC, 10% O, 90% N) in freely moving male and female wild-type (WT) C57BL6 and eNOS knock-out (eNOS-/-) mice. Exposure to HXC caused an array of responses (of similar magnitude and duration) in both male and female WT mice such as, rapid increases in frequency of breathing, tidal volume, minute ventilation and peak inspiratory and expiratory flows, that were subject to pronounced roll-off. The responses to HXC in male eNOS-/- mice were similar to male WT mice. In contrast, several of the ventilatory responses in female eNOS-/- mice (e.g., frequency of breathing, and expiratory drive) were greater compared to female WT mice. Upon return to room-air, male and female WT mice showed similar excitatory ventilatory responses (i.e., short-term potentiation phase). These responses were markedly reduced in male eNOS-/- mice, whereas female eNOS-/- mice displayed robust post-HXC responses that were similar to those in female WT mice. Our data demonstrates that eNOS plays important roles in (1) ventilatory responses to HXC in female compared to male C57BL6 mice; and (2) expression of post-HXC responses in male, but not female C57BL6 mice. These data support existing evidence that sex, and the functional roles of specific proteins (e.g., eNOS) have profound influences on ventilatory processes, including the responses to HXC.
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http://dx.doi.org/10.1038/s41598-021-97322-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443732PMC
September 2021

D-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception.

Sci Rep 2021 05 11;11(1):10038. Epub 2021 May 11.

Department of Pharmacology, Case Western Reserve University, Cleveland, OH, 44106, USA.

We have identified thiolesters that reverse the negative effects of opioids on breathing without compromising antinociception. Here we report the effects of D-cystine diethyl ester (D-cystine diEE) or D-cystine dimethyl ester (D-cystine diME) on morphine-induced changes in ventilation, arterial-blood gas chemistry, A-a gradient (index of gas-exchange in the lungs) and antinociception in freely moving rats. Injection of morphine (10 mg/kg, IV) elicited negative effects on breathing (e.g., depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive). Subsequent injection of D-cystine diEE (500 μmol/kg, IV) elicited an immediate and sustained reversal of these effects of morphine. Injection of morphine (10 mg/kg, IV) also elicited pronounced decreases in arterial blood pH, pO and sO accompanied by pronounced increases in pCO (all indicative of a decrease in ventilatory drive) and A-a gradient (mismatch in ventilation-perfusion in the lungs). These effects of morphine were reversed in an immediate and sustained fashion by D-cystine diME (500 μmol/kg, IV). Finally, the duration of morphine (5 and 10 mg/kg, IV) antinociception was augmented by D-cystine diEE. D-cystine diEE and D-cystine diME may be clinically useful agents that can effectively reverse the negative effects of morphine on breathing and gas-exchange in the lungs while promoting antinociception. Our study suggests that the D-cystine thiolesters are able to differentially modulate the intracellular signaling cascades that mediate morphine-induced ventilatory depression as opposed to those that mediate morphine-induced antinociception and sedation.
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http://dx.doi.org/10.1038/s41598-021-89455-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113454PMC
May 2021

Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia.

Sci Rep 2021 03 26;11(1):6985. Epub 2021 Mar 26.

Department of Pediatrics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106-4984, USA.

There is an urgent need to develop novel compounds that prevent the deleterious effects of opioids such as fentanyl on minute ventilation while, if possible, preserving the analgesic actions of the opioids. We report that L-glutathione ethyl ester (GSHee) may be such a novel compound. In this study, we measured tail flick latency (TFL), arterial blood gas (ABG) chemistry, Alveolar-arterial gradient, and ventilatory parameters by whole body plethysmography to determine the responses elicited by bolus injections of fentanyl (75 μg/kg, IV) in male adult Sprague-Dawley rats that had received a bolus injection of GSHee (100 μmol/kg, IV) 15 min previously. GSHee given alone had minimal effects on TFL, ABG chemistry and A-a gradient whereas it elicited changes in some ventilatory parameters such as an increase in breathing frequency. In vehicle-treated rats, fentanyl elicited (1) an increase in TFL, (2) decreases in pH, pO and sO and increases in pCO (all indicative of ventilatory depression), (3) an increase in Alveolar-arterial gradient (indicative of a mismatch in ventilation-perfusion in the lungs), and (4) changes in ventilatory parameters such as a reduction in tidal volume, that were indicative of pronounced ventilatory depression. In GSHee-pretreated rats, fentanyl elicited a more prolonged analgesia, relatively minor changes in ABG chemistry and Alveolar-arterial gradient, and a substantially milder depression of ventilation. GSHee may represent an effective member of a novel class of thiolester drugs that are able to prevent the ventilatory depressant effects elicited by powerful opioids such as fentanyl and their deleterious effects on gas-exchange in the lungs without compromising opioid analgesia.
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http://dx.doi.org/10.1038/s41598-021-86458-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997982PMC
March 2021

Enhanced non-eupneic breathing following hypoxic, hypercapnic or hypoxic-hypercapnic gas challenges in conscious mice.

Respir Physiol Neurobiol 2014 Dec 19;204:147-59. Epub 2014 Sep 19.

Department of Pediatrics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4984, USA. Electronic address:

C57BL6 mice display non-eupneic breathing and spontaneous apneas during wakefulness and sleep as well as markedly disordered breathing following cessation of a hypoxic challenge. We examined whether (1) C57BL6 mice display marked non-eupneic breathing following hypercapnic or hypoxic-hypercapnic challenges, and (2) compared the post-hypoxia changes in non-eupneic breathing of C57BL6 mice to those of B6AF1 (57BL6 dam × A/J sire) and Swiss-Webster mice, which display different ventilatory responses than C57BL6 mice. C57BL6 mice displayed marked increases in respiratory frequency and non-eupneic breathing upon return to room-air after hypoxic (10% O2, 90% N2), hypercapnic (5% CO2, 21% O2 and 74% N2) and hypoxic-hypercapnic (10% O2, 5% CO2 and 85% N2) challenges. B6AF1 mice displayed less tachypnea and reduced non-eupneic breathing post-hypoxia, whereas Swiss-Webster mice displayed robust tachypnea with minimal increases in non-eupneic breathing post-hypoxia. These studies demonstrate that non-eupneic breathing increases after physiologically-relevant hypoxic-hypercapnic challenge in C57BL6 mice and suggest that further studies with these and B6AF1 and Swiss-Webster mice will help define the genetics of non-eupneic breathing.
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http://dx.doi.org/10.1016/j.resp.2014.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252883PMC
December 2014

Morphine has latent deleterious effects on the ventilatory responses to a hypoxic challenge.

Open J Mol Integr Physiol 2013 Nov;3(4):166-180

Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

The aim of this study was to determine whether morphine depresses the ventilatory responses elicited by a hypoxic challenge (10% O, 90% N) in conscious rats at a time when the effects of morphine on arterial blood gas (ABG) chemistry, Alveolar-arterial (A-a) gradient and minute ventilation (V) had completely subsided. In vehicle-treated rats, each episode of hypoxia stimulated ventilatory function and the responses generally subsided during each normoxic period. Morphine (5 mg/kg, i.v.) induced an array of depressant effects on ABG chemistry, A-a gradient and V (via decreases in tidal volume). Despite resolution of these morphine-induced effects, the first episode of hypoxia elicited substantially smaller increases in V than in vehicle-treated rats, due mainly to smaller increases in frequency of breathing. The pattern of ventilatory responses during subsequent episodes of hypoxia and normoxia changed substantially in morphine-treated rats. It is evident that morphine has latent deleterious effects on ventilatory responses elicited by hypoxic challenge.
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http://dx.doi.org/10.4236/ojmip.2013.34022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103751PMC
November 2013

Morphine has latent deleterious effects on the ventilatory responses to a hypoxic-hypercapnic challenge.

Open J Mol Integr Physiol 2013 Aug;3(3):134-145

Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

This study explored the concept that morphine has latent deleterious actions on the ventilatory control systems that respond to a hypoxic-hypercapnic challenge. In this study, we examined the ventilatory responses elicited by hypoxic-hypercapnic challenge in conscious rats at a time when the effects of morphine (10 mg/kg) on arterial blood-gas chemistry and minute ventilation had subsided. Morphine induced pronounced changes in arterial blood-gas chemistry (e.g., an increase in pCO, decreases in pO and sO) and decreases in minute ventilation. Despite the complete resolution of the morphine-induced changes in arterial blood-gas chemistry and minute ventilation and almost complete resolution of the effects on peak inspiratory flow and peak expiratory flow, subsequent exposure to hypoxic-hypercapnic challenge elicited markedly blunted increases in minute ventilation and in peak inspiratory and expiratory flows. These findings demonstrate that (1) the changes in arterial blood-gas chemistry elicited by morphine parallel changes in minute ventilation rather than PIF and PEF, and (2) morphine has latent untoward effects on the ventilatory responses to hypoxic-hypercapnic challenge. These novel findings raise the possibility that patients deemed to have recovered from the acute ventilatory depressant effects of morphine may still be susceptible to the latent effects of this opioid analgesic. The mechanisms underlying these latent effects remain to be elucidated.
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http://dx.doi.org/10.4236/ojmip.2013.33019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103749PMC
August 2013

Low-dose morphine elicits ventilatory excitant and depressant responses in conscious rats: Role of peripheral μ-opioid receptors.

Open J Mol Integr Physiol 2013 Aug;3(3):111-124

Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

The systemic administration of morphine affects ventilation via a mixture of central and peripheral actions. The aims of this study were to characterize the ventilatory responses elicited by a low dose of morphine in conscious rats; to determine whether tolerance develops to these responses; and to determine the potential roles of peripheral μ-opioid receptors (μ-ORs) in these responses. Ventilatory parameters were monitored via unrestrained whole-body plethysmography. Conscious male Sprague-Dawley rats received an intravenous injection of vehicle or the peripherally-restricted μ-OR antagonist, naloxone methiodide (NLXmi), and then three successive injections of morphine (1 mg/kg) given 30 min apart. The first injection of morphine in vehicle-treated rats elicited an array of ventilatory excitant (i.e., increases in frequency of breathing, minute volume, respiratory drive, peak inspiratory and expiratory flows, accompanied by decreases in inspiratory time and end inspiratory pause) and inhibitory (i.e., a decrease in tidal volume and an increase in expiratory time) responses. Subsequent injections of morphine elicited progressively and substantially smaller responses. The pattern of ventilatory responses elicited by the first injection of morphine was substantially affected by pretreatment with NLXmi whereas NLXmi minimally affected the development of tolerance to these responses. Low-dose morphine elicits an array of ventilatory excitant and depressant effects in conscious rats that are subject to the development of tolerance. Many of these initial actions of morphine appear to involve activation of peripheral μ-ORs whereas the development of tolerance to these responses does not.
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http://dx.doi.org/10.4236/ojmip.2013.33017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041292PMC
August 2013

Essential role of hemoglobin beta-93-cysteine in posthypoxia facilitation of breathing in conscious mice.

J Appl Physiol (1985) 2014 May 7;116(10):1290-9. Epub 2014 Mar 7.

Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, Ohio.

When erythrocyte hemoglobin (Hb) is fully saturated with O2, nitric oxide (NO) covalently binds to the cysteine 93 residue of the Hb β-chain (B93-CYS), forming S-nitrosohemoglobin. Binding of NO is allosterically coupled to the O2 saturation of Hb. As saturation falls, the NO group on B93-CYS is transferred to thiols in the erythrocyte, and in the plasma, forming circulating S-nitrosothiols. Here, we studied whether the changes in ventilation during and following exposure to a hypoxic challenge were dependent on erythrocytic B93-CYS. Studies were performed in conscious mice in which native murine Hb was replaced with human Hb (hB93-CYS mice) and in mice in which murine Hb was replaced with human Hb containing an alanine rather than cysteine at position 93 on the Bchain (hB93-ALA). Both strains expressed human γ-chain Hb, likely allowing a residual element of S-nitrosothiol-dependent signaling. While resting parameters and initial hypoxic (10% O2, 90% N2) ventilatory responses were similar in hB93-CYS mice and hB93-ALA mice, the excitatory ventilatory responses (short-term potentiation) that occurred once the mice were returned to room air were markedly diminished in hB93-ALA mice. Further, short-term potentiation responses were virtually absent in mice with bilateral transection of the carotid sinus nerves. These data demonstrate that hB93-CYS plays an essential role in mediating carotid sinus nerve-dependent short-term potentiation, an important mechanism for recovery from acute hypoxia.
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http://dx.doi.org/10.1152/japplphysiol.01050.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4044395PMC
May 2014

Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats.

Respir Physiol Neurobiol 2014 Jan 24;191:95-105. Epub 2013 Nov 24.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106-4984, USA. Electronic address:

This study determined the effects of the peripherally restricted μ-opiate receptor (μ-OR) antagonist, naloxone methiodide (NLXmi) on fentanyl (25μg/kg, i.v.)-induced changes in (1) analgesia, (2) arterial blood gas chemistry (ABG) and alveolar-arterial gradient (A-a gradient), and (3) ventilatory parameters, in conscious rats. The fentanyl-induced increase in analgesia was minimally affected by a 1.5mg/kg of NLXmi but was attenuated by a 5.0mg/kg dose. Fentanyl decreased arterial blood pH, pO2 and sO2 and increased pCO2 and A-a gradient. These responses were markedly diminished in NLXmi (1.5mg/kg)-pretreated rats. Fentanyl caused ventilatory depression (e.g., decreases in tidal volume and peak inspiratory flow). Pretreatment with NLXmi (1.5mg/kg, i.v.) antagonized the fentanyl decrease in tidal volume but minimally affected the other responses. These findings suggest that (1) the analgesia and ventilatory depression caused by fentanyl involve peripheral μ-ORs and (2) NLXmi prevents the fentanyl effects on ABG by blocking the negative actions of the opioid on tidal volume and A-a gradient.
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http://dx.doi.org/10.1016/j.resp.2013.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391496PMC
January 2014

Co-activation of μ- and δ-opioid receptors elicits tolerance to morphine-induced ventilatory depression via generation of peroxynitrite.

Respir Physiol Neurobiol 2013 May 5;186(3):255-64. Epub 2013 Mar 5.

Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

We determined whether pretreatment with (1) the μ-/δ-opioid receptor (μ-/δ-OR) antagonist, naloxone, (2) the δ1,2-OR antagonist, naltrindole, or (3) the peroxynitrite scavenger, d-penicillamine, affects the development of tolerance to the ventilatory depressant effects of morphine in rats. The injection of morphine in vehicle-pretreated rats decreased minute ventilation predominantly via decreases in tidal volume. Pretreatment with naloxone blunted the responses to morphine whereas pretreatment with naltrindole or d-penicillamine did not. A second injection of morphine, given one day later, elicited markedly smaller responses in vehicle rats whereas it elicited pronounced ventilatory depression in rats that were pretreated with naloxone, naltrindole or d-penicillamine (prior to morphine) the day before. Moreover, the ventilatory responses elicited by subsequent exposure to a hypoxic-hypercapnic challenge were markedly depressed in naloxone- or d-penicillamine-pretreated rats compared to vehicle-pretreated rats. These findings suggest that activation of μ- and δ-ORs causes tolerance to the ventilatory depressant effects of morphine at least partly via the generation of peroxynitrite.
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http://dx.doi.org/10.1016/j.resp.2013.02.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451624PMC
May 2013

Hypoxia-induced ventilatory responses in conscious mice: gender differences in ventilatory roll-off and facilitation.

Respir Physiol Neurobiol 2013 Feb 24;185(3):497-505. Epub 2012 Nov 24.

Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

The aim of this study was to compare the ventilatory responses of C57BL6 female and male mice during a 15 min exposure to a hypoxic-hypercapnic (H-H) or a hypoxic (10% O(2), 90% N(2)) challenge and subsequent return to room air. The ventilatory responses to H-H were similar in males and females whereas there were pronounced gender differences in the ventilatory responses during and following hypoxic challenge. In males, the hypoxic response included initial increases in minute volume via increases in tidal volume and frequency of breathing. These responses declined substantially (roll-off) during hypoxic exposure. Upon return to room-air, relatively sustained increases in these ventilatory parameters (short-term potentiation) were observed. In females, the initial responses to hypoxia were similar to those in males whereas roll-off was greater and post-hypoxia facilitation was smaller than in males. The marked differences in ventilatory roll-off and post-hypoxia facilitation between female and male C57BL6 mice provide evidence that gender is of vital importance to ventilatory control.
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http://dx.doi.org/10.1016/j.resp.2012.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593587PMC
February 2013

Ventilatory responses during and following exposure to a hypoxic challenge in conscious mice deficient or null in S-nitrosoglutathione reductase.

Respir Physiol Neurobiol 2013 Feb 24;185(3):571-81. Epub 2012 Nov 24.

Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

Exposure to a hypoxic challenge increases ventilation in wild-type (WT) mice that diminish during the challenge (roll-off) whereas return to room air causes an increase in ventilation (short-term facilitation, STF). Since plasma and tissue levels of ventilatory excitant S-nitrosothiols such as S-nitrosoglutathione (GSNO) increase during hypoxia, this study examined whether (1) the initial increase in ventilation is due to generation of GSNO, (2) roll-off is due to increased activity of the GSNO degrading enzyme, GSNO reductase (GSNOR), and (3) STF is limited by GSNOR activity. Initial ventilatory responses to hypoxic challenge (10% O(2), 90% N(2)) were similar in WT, GSNO+/- and GSNO-/- mice. These responses diminished markedly during hypoxic challenge in WT mice whereas there was minimal roll-off in GSNOR+/- and GSNOR-/- mice. Finally, STF was greater in GSNOR+/- and GSNOR-/- mice than in WT mice (especially females). This study suggests that GSNOR degradation of GSNO is a vital step in the expression of ventilatory roll-off and that GSNOR suppresses STF.
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http://dx.doi.org/10.1016/j.resp.2012.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593598PMC
February 2013
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